Long-lasting and degradable implant compositions

ABSTRACT

Described are methods for reversible occlusion of a body lumen by way of degradation as a result of exposure to one or more stimuli such as light. The methods include administering one or more substance(s) into a body lumen of a subject and forming a stimuli-responsive polymer mass in the body lumen from the one or more substance(s). The mass is sufficient to occlude the body lumen in a manner that prevents transport of at least one material through the body lumen and is susceptible to on-command reversal in the body lumen upon exposure to one or more stimuli. The methods include administering one or more stimuli to a polymer mass in a body lumen for a time and intensity to cause the reverse the polymer mass. The methods are particular useful for applications in which it is desirable to temporarily occlude a body lumen, such as male and female contraception.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation-in-Part (CIP) of U.S. patentapplication Ser. No. 15/863,759 filed Jan. 5, 2018 and published as U.S.Patent Application Publication No. 20180185096 on Jul. 5, 2018. The '759application relies on the disclosure of and claims priority to and thebenefit of the filing date of U.S. Provisional Application No.62/566,592 filed Oct. 2, 2017 and U.S. Provisional Application No.62/442,583, filed Jan. 5, 2017. This application is also related toInternational Application No. PCT/US2016/061671, filed Nov. 11, 2016 andpublished as WO/2017/083753 on May 18, 2017; U.S. patent applicationSer. No. 15/349,806, filed Nov. 11, 2016 and published as U.S. PatentApplication Publication No. 20170136144 on May 18, 2017; and U.S. patentapplication Ser. No. 15/349,824, filed Nov. 11, 2016 and published asU.S. Patent Application Publication No. 20170136143 on May 18, 2017. Thedisclosures of each of these applications are hereby incorporated byreference in their entireties.

BACKGROUND OF THE INVENTION Field of the Invention

Embodiments of the present invention are directed to the field ofocclusive materials and methods of occlusion. More particularly,embodiments of the present invention are directed to methods forreversible occlusion by way of degradation as a result of exposure tolight or through other stimuli. Further, embodiments of the inventioninclude stimuli-responsive materials which can be useful for reversiblecontraception, embolization, sealants, tissue fillers, or on-commanddrug delivery.

Description of Related Art

Except for intra uterine devices (IUDs), the contraceptive field lacksmethods that are long-lasting and reversible at a later point in time.In addition, the only contraceptives men have available to them arecondoms and vasectomy. Vasectomy is a procedure for producing malecontraception which involves severing the vas deferens. Potentialcomplications of vasectomy include bleeding at the site of the surgicalprocedure, which may cause swelling or bruising; infection at the siteof the incision; infection in the scrotum; sperm granuloma; congestiveepididymitis; recanalization; and the inability to reverse thevasectomy. Additionally, a portion of patients report pain after theprocedure. Possibly the largest deterring factor of vasectomy, besidesthe surgical nature of the procedure, is the difficulty of reversing thevasectomy. The procedure, known as vasovasostomy, is a three to fourhours long, expensive microsurgical procedure in which the patient isunder general anesthesia. Further, a vasovasostomy does not guaranteethe man restores his fertility due to the presence of anti-spermantibodies that persist in the body after the vasovasostomy.

Due to these potential complications and difficulty in reversing theprocedure, alternative procedures for long-lasting, reversible malecontraception have been explored. One strategy that has been the subjectof research and development is vas-occlusive contraception, whichinvolves injecting or implanting a substance into the vas deferens lumento occlude this vessel so that the flow of sperm cells from theepididymis is blocked. Particular examples include RISUG, which involvesimplantation of styrene maleic anhydride, VASALGEL, as well aspolyurethane and silicone implants. However, technical barriers forsuccessfully introducing these procedures into the male contraceptivearmamentarium have been documented. All prior attempts of reversingvas-occlusive contraceptives have utilized invasive methods such asinjecting a solution into the vas deferens to dislodge, de-precipitate,or dissolve the implant, or physically breaking apart the gel viavibration or electric stimulation. These reversal methods have worked insmaller animals, but have failed in larger animals such as canines andnon-human primates. To date, a safe and effective method ofvas-occlusion reversal that works cross-species has not been shown.Furthermore, minimally-invasive or non-invasive method for vas-occlusionreversal has not been reported. Similarly, there have been attempts forocclusion of the fallopian tubes for female contraception. Inparticular, ESSURE was a coil implanted into each fallopian tube, and byinducing fibrosis, it blocked the tubes and prevented fertilization.FEMBLOC, a contraceptive in development, involves implanting abiopolymer into the fallopian tubes; similar to ESSURE, FEMBLOC resultsin permanent occlusion of the tubes. Given their permanent effects,these methods may serve as alternatives to tubal ligations. However, aneasily reversible fallopian occlusion device could serve as an effectiveand safe alternative to intra uterine devices (IUD's) and would benon-hormonal.

Currently, there are no on-command reversible materials that areFDA-approved. There is a need in the art for materials that can form anocclusion in a body lumen and be reversed through a safe and effectivemethod at a later point in time.

SUMMARY OF THE INVENTION

Embodiments of the invention include methods for reversible occlusion ofa body lumen by way of degradation as a result of exposure to one ormore stimuli such as light. The methods are particular useful forapplications in which it is desirable to temporarily occlude a bodylumen, such as for contraception. Further, embodiments of the inventioninclude stimuli-responsive materials which can be useful for reversibleembolization, sealants, tissue fillers, contraception, or on-commanddrug delivery.

Specific aspects of embodiments of the invention include Aspect 1, whichis a method comprising (a) administering one or more substance(s) into abody lumen of a subject; and (b) forming a stimuli-responsive polymermass in the body lumen from the one or more substance(s); (c) whereinthe mass i s sufficient to occlude the body lumen in a manner thatprevents transport of at least one material through the body lumen; and(d) wherein the polymer mass is susceptible to on-command reversal inthe body lumen upon exposure to one or more stimuli such that after thereversal is performed, the polymer mass no longer occludes the bodylumen.

Aspect 2 is a method of Aspect 1, wherein the stimulus is one or more ofultrasound, x-ray, ultraviolet, visible, near infrared, infrared,thermal, magnetic, electric, heat, vibrations, mechanical, aqueoussolutions (neutral, basic, or acidic), organic solvent, aqueous-organicmixture, enzymatic, protein(s), peptide(s), small organic molecules,large organic molecules, nanoparticles, microparticles, quantum dots,carbon-based materials, and/or any combination thereof.

Aspect 3 is a method of any one of the preceding Aspects, wherein thebody lumen comprises an artery, vein, capillary, lymphatic vessel, a vasdeferens, epididymis, or a fallopian tube; a duct including a bile duct,a hepatic duct, a cystic duct, a pancreatic duct, or a parotid duct; anorgan including a uterus, prostate, or any organ of the gastrointestinaltract or circulatory system or respiratory system or nervous system; asubcutaneous space; or an interstitial space.

Aspect 4 is a method of any one of the preceding Aspects, wherein the atleast one material is a sperm cell and the body lumen is a vas deferens.

Aspect 5 is a method of any one of the preceding Aspects, wherein the atleast one material is an oocyte and the body lumen is a fallopian tube.

Aspect 6 is a method of any one of the preceding Aspects, wherein one ormore substance(s) is a polymeric precursor material.

Aspect 7 is a method of any one of the preceding Aspects, wherein thepolymeric precursor material comprises natural or synthetic monomers,polymers or copolymers, biocompatible monomers, polymers or copolymerssuch as, but not limited to: polystyrene, neoprene, polyetherether 10ketone (PEEK), carbon reinforced PEEK, polyphenylene,potyetherketoneketone (PEKK), polyaryletherketone (PAEK),polyphenylsulphone, polysulphone, polyurethane, polyethylene,low-density polyethylene (LDPE), linear low-density polyethylene(LLDPE), high-density polyethylene (HDPE), polypropylene,polyetherketoneetherketoneketone (PEKEKK), nylon, fluoropolymers such aspolytetrafluoroethylene (PTFE or TEFLON®), TEFLON® TFE(tetrafluoroethylene), polyethylene terephthalate (PET or PETE), TEFLON®FEP (fluorinated ethylene propylene), TEFLON® PEA (perfluoroalkoxyalkane), and/or polymethylpentene (PMP) styrene maleic anhydride,styrene maleic acid (SMA), polyurethane, silicone, polymethylmethacrylate, polyacrylonitrile, poly (carbonate-urethane), poly(vinylacetate), nitrocellulose, cellulose acetate, urethane,urethane/carbonate, polylactic acid, polya.crylami de (PAAM), poly(N-isopropylacrylamine) (PNIPAM), poly (vinylmethylether), poly(ethylene oxide), poly (ethyl (hydroxyethyl) cellulose), poly(2-ethyloxazoline), polylactide (PLA), potyglycoli de (PGA.),poly(lactide-co-glycolide) PLEA, poly(e-caprolactone), polydiaoxanone,polyanhydride, trimethylene carbonate, poly(P-hydroxybutyrate),poly(g-ethyl glutamate), pol:v(DTH-iminocarbonate), poly(bisphenol Aiminocarbonate), poly(orthoester) (POE), polycyanoacrylate (PCA),polyphosphazene, polyethyleneoxide (PEO), polyethylene glycol (PEG) orany of its derivatives, polyacrylacid (PAA), polyacrylonitrile (PAN),polyvinylacrylate (PVA), polyvinylpyrrolidone (PVP), polyglycolic lacticacid (PGLA), poly(2-hydroxypropyl metha.crylamide) (pHIPMAm), poly(vinylalcdhol) (PVOH), PEG diacrylate (PUMA), poly(hydroxyethyl methacrylate)(pHEMA), N-isopropylacrylamide (WA), poly(vinyl alcohol) poly(acrylicacid) (PVOH-PAA), collagen, silk, fibrin, gelatin, hyaluron, cellulose,chitin, dextran, casein, albumin, ovalbumin, heparin sulfate, starch,agar, heparin, alginate, fibronectin, fibrin, keratin, pectin, elastin,ethylene vinyl acetate, ethylene vinyl alcohol (EVOH), polyethyleneoxide, PLA or PLLA (poly(L-lactide) or poly(t-lactic acid)),poly(D,L-lactic acid), poly(D,L-lactide), pol:vdimethylsiloxane ordimethicone (PDMS), poly(isopropyl acr:vlate) (PIPA), polyethylene vinylacetate (PEVA), PEG styrene, polytetrafluoroethylene RFE such as TEFLON®RFE or KRYTOX® RFT, fluorinated polyethylene (FLPE or NALGENER), methylpalmitate, temperature responsive polymers such aspoly(N-isopropylacrylamide) (NWA), polycarbonate, polyethersulfone, poiycaprolactone, polymethyl methacrylate, polyisobutylene, nitrocellulose,medical grade silicone, cellulose acetate, cellulose acetate butyrate,polyacrylonitrile, poly(lactide-co-caprolactone (PLCL), and/or chitosan.

Aspect 8 is a method of any one of the preceding Aspects, wherein themass is a hydrogel.

Aspect 9 is a method of any one of the preceding Aspects, wherein thesubstances) are injected through a multi-syringe system to form themass.

Aspect 10 is a method of any one of the preceding Aspects, wherein thesubstance(s injected through a needle or catheter or combination ofboth.

Aspect 11 is a method of any one of the preceding Aspects, wherein thesubstance(s) are injected through a needle or catheter or combination.

Aspect 12 is a method of any one of the preceding Aspects, wherein theone or more substance(s) form the polymer mass by way of a bioorthogonalreaction.

Aspect 13 is a method of any one of the preceding Aspects, wherein theone or more substance(s) comprises one or more photolahile moieties.

Aspect 14 is a method of any one of the preceding Aspects, wherein theone or more substance(s) comprises one more photolabile moieties linkedtogether.

Aspect 15 is a method of any one of the preceding Aspects, wherein thephotolahile moiety is incorporated into the one or more substance(s)through a linkage to a heteroatom, such as oxygen, sulfur, or nitrogen,as an ether, thioester, ester, or amide or amine.

Aspect 16 is a method of any one of the preceding Aspects, wherein theone or more substance(s) comprise a photolabile moiety chosen from oneor more of 2-nitrobenzyl, a-bromo-2-nitrotoluene, 2 nitrohenzylchloride, 5-methyl-2-nitrobenzyl alcdhol, 5-hydroxy-2-nitrobenzylalcohol, 4,5 dimethoxy-2-nitrobenzyl alcohol,4,5-dimethoxy-2-nitrobenzyl chloroformate, 4,5-dimethoxy-2-nitrobenzylbromide, 5-chloro-2-nitrobenzyl alcohol, 5-methyl-2-nitrobenzylchloride, 4-chloro-2-nitrobenzyl alcohol, 2-nitrobenzyl alcohol,4-chloro-2-nitrobenzyl chloride, 4-fluoro-2nitrobenzyl bromide,5-fluoro-2-nitrobenzyl alcohol, and 2-methyl-3-nitrobenzyl alcohol, 2hydroxy-5-nitrobenzyl alcohol, 2-hydroxy-5-nitrobenzyl bromide,2-methoxy-5-nitrobenzyl bromide, 2-chloro-5-nitrobenzyl alcohol,2-fluoro-5-nitrobenzyl alcohol, 2-methyl-3-nitrobenzyl chloride, and2-acetoxy-5-nitrobenzyl chloride, such as4-[4-(1-Hydroxyethyl)-2-methoxy-5-nitrophenoxy]butanoic acid,α-carboxy-2-nitrobenzyl (CNB), 1-(2-nitrophenyl)ethyl (NPE), 4,5dimethoxy-2-nitrobenzyl (DMNB), 1-(4,5-dimethoxy-2-nitrophenyl)ethyl(DMNPE), 5 carboxymethoxy-2-nitrobenzyl (CMNB), nitrophenyl (NP), or anyof their derivatives, or the photolabile moiety is derived from one ormore of benzoin, phenacyl, coumaryl, arylmethyl, thiopixyl, orarylsulfonamides, such as a 1-o-phenylethyl ester, 1-o-nitrophenylethyl,or any of their derivatives, such as a 1-o-phenylethyl ester with anorder of magnitude faster degradation than o-nitrobenzyl ester, or thephotolabile moiety is O-o-nitrobenzyl o′, o″-diethyl phosphate.

Aspect 17 is a method of any one of the preceding Aspects, wherein theone or more stimuli comprises light.

Aspect 18 is a method of any one of the preceding Aspects, wherein thelight is monochromatic, ultraviolet, infrared, or visible light.

Aspect 19 is a method of any one of the preceding Aspects, wherein thelight is administered through tissue overlying the body lumen.

Aspect 20 is a method of any one of the preceding Aspects, wherein thelight is administered by way of a catheter or needle placed in the bodylumen.

Aspect 21 is a method of any one of the preceding Aspects, wherein theneedle or catheter comprises multiple lumens, such as two or morelumens, with a second lumen capable of delivering a second stimulus.

Aspect 22 is a method of any one of the preceding Aspects, wherein thelight has an energy which ranges from 0.01-40J/cm², such as from0.1-7J/cm², or from 0.2-6J/cm², or less than 2.0J/cm².

Aspect 23 is a method of any one of the preceding Aspects, wherein thelight has a wavelength ranging from 200 nm to 2,500 nm, such as from 250nm to 450 nm, or from 300 nm to 425 nm, or from 330 nm to 420 nm, orfrom 350 nm to 390 nm, or from 365 nm to 405 nm, or from 330 and 460 nm,or from 370 and 440 nm, or from 405 nm to 500 nm, or from 500 nm to 800nm, or from 700 nm to 2,500 nm.

Aspect 24 is a method of any one of the preceding Aspects, furthercomprising applying one or more stimuli to the polymer mass to reversethe polymer mass.

Aspect 25 is a method of any one of the preceding Aspects, wherein oneor more stimuli change the chemical structure and/or function of theimplant.

Aspect 26 is a method of any one of the preceding Aspects, wherein theone or more stimuli comprise a chemical compound which is delivered tothe polymer mass and initiates a reverse crosslinking (e.g. Click orbioorthogonal) reaction to depolymerize the polymer mass.

Aspect 27 is a method of any one of the preceding Aspects, wherein theone or more stimuli comprise an enzyme which catalyzes depolymerizationof the polymer mass.

Aspect 28 is a method of any one of the preceding Aspects, whereinreversal of the polymer mass restores the flow of fluid, cells, and/orproteins within the body lumen.

Aspect 29 is a method of any one of the preceding Aspects, furthercomprising administration of light after administration of the one ormore substance(s) to catalyze formation of the polymer mass.

Aspect 30 is a method of any one of the preceding Aspects, furthercomprising administration of light after formation of the polymer massto reverse the polymer mass.

Aspect 31 is a method of any one of the preceding Aspects, wherein theadministration of light required to catalyze formation of the polymermass is a different wavelength than the wavelength to reverse thepolymer mass.

Aspect 32 is a method comprising administering one or more stimuli to apolymer mass in a body lumen for a time and intensity to cause thepolymer mass to deteriorate, break down, degrade, disintegrate,dissolve, destroy, remove, dislodge, de precipitate, liquefy, flushand/or reduce in whole or part, thereby reversing the polymer mass.

Aspect 33 is a method of any one of the preceding Aspects, wherein theone or more stimuli comprise one or more of ultrasound, x ray,ultraviolet, visible, near infrared, infrared, thermal, magnetic,electric, heat, vibrations, mechanical, aqueous solutions (neutral,basic, or acidic), organic solvent, aqueous-organic mixture, enzymatic,protein(s), peptide(s), small organic molecules, large organicmolecules, nanoparticles, microparticles, quantum dots, carbon-basedmaterials, and/or any combination thereof.

Aspect 34 is a method of any one of the preceding Aspects, wherein thebody lumen comprises an artery, vein, capillary, lymphatic vessel, a vasdeferens, epididymis, or a fallopian tube; a duct including a bile duct,a hepatic duct, a cystic duct, a pancreatic duct, or a parotid duct; anorgan including a uterus, prostate, or any organ of the gastrointestinaltract or circulatory system or respiratory system or nervous system; asubcutaneous space; or an interstitial space.

Aspect 35 is a method of any one of the preceding Aspects, wherein thebody lumen is a vas deferens.

Aspect 36 is a method of any one of the preceding Aspects, wherein thebody lumen is a fallopian tube.

Aspect 37 is a method of any one of the preceding Aspects, wherein asaline flush is performed after administration of the one or morestimulus to assist in removing the occlusion from the body lumen.

Aspect 38 is a method of any one of the preceding Aspects, wherein thepolymer mass is capable of degradation within 1-60 minutes of beingexposed to the one or more stimuli.

Aspect 39 is a method of any one of the preceding Aspects, wherein themechanical properties e.g. G′ (storage modulus) or G″ (loss modulus) ofthe polymer mass is altered after administration of the one or morestimuli.

Aspect 40 is a method of any one of the preceding Aspects, wherein theviscosity of the polymer mass is altered after administration of the oneor more stimuli.

Aspect 41 is a method of any one of the preceding Aspects, wherein thepolymer mass swells or shrinks after administration of the one or morestimuli.

Aspect 42 is a method of any one of the preceding Aspects, wherein theporosity or mesh size of the polymer mass is altered afteradministration of the one or more stimuli.

Aspect 43 is a method of any one of the preceding Aspects, wherein oneor more steps of the method are guided by an imaging modality comprisingultrasound, x-ray, fluoroscopy, or CI', or any combination of these.

Aspect 44 is a method of any one of the preceding Aspects, whereinreversal of the polymer mass is confirmed by an imaging modalitycomprising ultrasound, x-ray, fluoroscopy, MRI, or CT, or anycombination of these.

Aspect 45 is a method of any one of the preceding Aspects, wherein thepolymer mass comprises one or more factors and reversal of the polymermass causes a release of the one or more factors.

Aspect 46 is a method of any one of the preceding Aspects, wherein thefactors are chosen from one or more of spermicidal agents, fertilityagents, hormones, growth factors, anti-inflammatory drugs,anti-bacterial agents, anti-viral agents, adherent proteins, antibodies,antibody-drug conjugates, contrast agents, imaging agents, therapeuticdrugs, antimicrobials, vasodilators, steroids, ionic solutions,proteins, nucleic acids, antibodies, or fragments thereof.

Aspect 47 is a method of any one of the preceding Aspects, wherein theone or more stimuli comprises light.

Aspect 48 is a method of any one of the preceding Aspects, wherein thelight is monochromatic, ultraviolet, visible, near infrared, or infraredlight.

Aspect 49 is a method of any one of the preceding Aspects, wherein thelight is administered through tissue overlying the body lumen.

Aspect 50 is a method of any one of the preceding Aspects, wherein thelight is administered by way of a catheter or needle placed in the bodylumen.

Aspect 51 is a method of any one of the preceding Aspects, wherein thelight has an energy which ranges from 0.01-40J/cm², including from0.1-7J/cm², or from 0.2-6J/cm², or less than 20J/cm².

Aspect 52 is a method of any one of the preceding Aspects, wherein thelight has a. wavelength ranging from 200 nm to 2,500 nm, including from250 nm to 450 nm, or from 300 nm to 425 nm, or from 330 nm to 420 nm, orfrom 350 nm to 390 nm, or from 365 nm to 405 nm, or from 330 and 460 nm,or from 370 and 440 nm, or from 405 nm to 500 nm, or from 500 nm to 800nm, or from 700 nm to 2,500 nm.

Aspect 53 is a method of any one of the preceding Aspects, wherein theone or more substance(s) comprises one or more photolabile moieties.

Aspect 54 is a method of any one of the preceding Aspects, wherein theone or more substance(comprises one more photolabile moieties linkedtogether.

Aspect 55 is a method of any one of the preceding Aspects, wherein theone or more photolabile moieties are incorporated into the one or moresubstance(s) through a linkage to a heteroatom, including an oxygenatom, a sulfur atom, or a nitrogen atom, or as an ether, thioether,ester, amide, or amine.

Aspect 56 is a method of any one of the preceding Aspects, wherein theone or more substance(s) comprise one or more photolabile moietieschosen from one or more of 2-nitrobenzyl, a-bromo-2-nitrotoluene,2-nitrobenzyl chloride, 5-methyl-2-nitrobenzyl alcohol,5-hydroxy-2-nitrobenzyl alcohol, 4,5-dimethoxy-2-nitrobenzyl alcohol,4,5-dimethoxy-2-nitrobenzyl chlorofonnate, 4,5-dimethoxy-2-nitrobenzylbromide, 5-chloro-2-nitrobenzyl alcohol, 5-methyl-2-nitrobenzylchloride, 4-chloro-2-nitrobenzyl alcohol, 2-nitrobenzyl alcohol,4-chloro-2-nitrobenzyl chloride, 4-fluoro-2nitrobenzyl bromide,5-fluoro-2-nitrobenzyl alcohol, and 2-methyl-3-nitrobenzyl alcohol,2-hydroxy-5-nitrobenzyl alcohol, 2-hydroxy-5-nitrobenzyl bromide,2-methoxy-5-nitrobenzyl bromide, 2-chloro-5-nitrobenzyl alcohol,2-fluoro-5-nitrobenzyl alcohol, 2-methyl-3-nitrobenzyl chloride, and2-acetoxy-5-nitrobenzyl chloride, such as4-[4-(1-hydroxyethyl)-2-methoxy-5-nitrophenoxylbutanoic acid,α-carboxy-2-nitrobenzyl (CNB), 1(2-nitrophenyl)ethy (NPE), 4,5-dimethoxy-2-nitrobenzyl (DMNB), 1-(4,5-di methoxy-2-nitrophenyl)ethyl(DMNPE), 5-carboxymethoxy-2-nitrobenzyl (CMNB), nitrophenyl (NP), or anyof their derivatives, or the photolabile moiety is derived from one ormore of benzoin, phenacyl, coumaryl, arylmethyl, thiopixyl, orarylsulfonamides, including a 1-o-phenylethyl ester,1-o-nitrophenylethyl, or any of their derivatives, including a1-o-phenylethyl ester with an order of magnitude faster degradation thano-nitrobenzyl ester, or the photolabile moiety is O-o-Nitrobenzyl O′,O″-diethyl phosphate.

Aspects of embodiments of the invention further include the followingAspects, such as Aspect 1A, a composition comprising: one or morespecies with a diameter of less than 1 um in solvent; wherein the one ormore species are capable of forming an implantable network with pores ofless than or equal to 3 μm, wherein the one or more species and/or theimplantable network are capable of being injected into a bodily lumen;and wherein the implantable network has a life-span of 6 months orgreater in vivo.

Embodiments include Aspect 2A, a composition for an occlusive implantcomprising: a multi-arm polyethylene glycol terminated with thiolcrosslinked with a multi-arm polyethylene glycol terminated with amaleimide; and wherein the composition is in a form capable of beingextruded from a needle.

Aspect 3A, a composition for an occlusive implant comprising: amulti-arm polyethylene glycol terminated with a thiol crosslinked insitu with a multi-arm polyethylene glycol terminated with a maleimide.

Aspect 4A is the composition of Aspect 1A, wherein one or more of thespecies comprises one or more of natural or synthetic monomers,polymers, copolymers or block copolymers, biocompatible monomers,polymers, copolymers or block copolymers, polystyrene, neoprene,polyetherether 10 ketone (PEEK), carbon reinforced REEK, polyphenylene,polyetherketoneketone (PEKK), polyaryletherketone (PAEK),polyphenylsulphone, potysulphone, polyurethane, polyethylene,low-density polyethylene (LDPE), linear low-density polyethylene(LLDPE), high-density polyethylene (HDPE), polypropylene,polyetherketoneetherketoneketone (PEKEKK), nylon, fluoropolymers,polytetrafluoroethylene (PUT or TEFLON®), TEFLON® TFE(tetrafluoroethylene), polyethylene terephthalate (PET or PETE), TEFLON®FEP (fluorinated ethylene propylene), TEFLON® PFA (perfluoroalkoxyalkane), and/or polymethylpentene (PMP) styrene maleic anhydride,styrene maleic acid (SMA), polyurethane, silicone, polytnethylmethacrylate, polyacrylonitrile, poly (carbonate-urethane), poly(vinylacetate), nitrocellulose, cellulose acetate, urethane,urethane/carbonate, polylactic acid, polyacrylamide (PAAM), poly(N-isopropylacrylamine) (PNIPAM), poly (vinylmethylether), poly(ethylene oxide), poly (ethyl (hydroxyethyl) cellulose), polyoxazoline(POx), polylactide (PLA), polyglycolide (PGA),poly(lactide-co-glycolide) PLGA, poly(e-caprolactone), poiydiaoxanone,polyanhydtide, trimethylene carbonate, poly(β-hydroxybutyrate),poly(g-ethyl glutamate), poly(DTH-iminocarbonate), poly(bisphenol Aiminocarbonate), poly(orthoester) (POE), polycyanoactylate (PCA),polyphosphazene, polyethyleneoxide (PEO), polyethyleneglycol (PEG) orany of its derivatives, polyacrylacid (PAA), polyacrylonitrile (PAN),polyvinylacrylate (PVA), polyvinylpyrrolidone (PVP), polyglycolic lacticacid (PGLA), poly(2-hydroxypropyl methacryl amide) (pEIPMAm), poly(vinylalcohol) CPVOH), PEG diacrylate (PEGDA), poly(hydroxyethyl methacrylate)(pHEMA), N-isopropylacrylamide (NIPA), poty(vinyl alcohol) polly(acrylicacid) (PVOH-PAA), collagen, silk, fibrin, gelatin, hyaluron, cellulose,chitin, dextran, casein, albumin, ovalbumin, heparin sulfate, starch,agar, heparin, alginate, fibronectin, fibrin, keratin, pectin, elastin,ethylene vinyl acetate, ethylene vinyl alcohol (EVOH), polyethyleneoxide, PLA or PLLA (poly(L-lactide) or pol(I -lactic acid)),poly(D.L-lactic acid), poly(D,L-lactide), polydimethylsiloxane ordimethicone (PDMS), poly(isopropyl acrylate) (PIPA), polyethylene vinylacetate (PEVA), PEG styrene, polytetraflurorethylene RFE, TEFLON® RFE,KRYTOX® RFE, fluorinated polyethylene (FLPE or NALGENE®), methylpalmitate, temperature responsive polymers, poly(N-isopropylacrylamide)(NIPA), polycarbonate, polyethersulfone, pol:_(s)7ca.prolactone,polymethyl methacrylate, polyisobutylene, nitrocellulose, medical gradesilicone, cellulose acetate, cellulose acetate butyrate,polyacrylonitrile, poly(lactide-co-caprolactone (PLCL), and/or chitosan.

Aspect 5A is the composition of Aspect 1A or 4A, wherein one or more ofthe species is functionalized with a group, including but not limitedto, acetic acid, acetylene, acrylate, alkyl, free amine, amine (HClsalt), ATRP initiator, azide, biotin, butyrate, carboxylic acid,chloroformate, epoxide, hydroxyl, isocyanate, methacrylate, nitrophenylcarbonate, NHS ester, aminooxy, polycaprolactone, polylactide, propionicacid, RAFT CTA, succinimidyl, succinimidyl carboxymethyl, succinimidylglutaramide, succinimidyl glutarate, thiol, tosylate, vinyl ether,vinylsulfone, and/or bis-MPA Dendron.

Aspect 6A is the composition of any of Aspect 1A, 4A or 5A, wherein oneor more of the species is heterobifunctional, homobifunctional,monofunctional, dendritner, multi-arm, block co-polymer, or randomco-polymer.

Aspect 7A is the composition of any of Aspects 1A or 4A-6A, wherein oneor more of the species are capable of crosslinking.

Aspect 8A is the composition of any of Aspects 1A or 4A-7A, wherein oneor more of the species are capable of crosslinking and forming anitnpla.ntable network by way of a bio-orthogonal reaction.

Aspect 9A is the composition of any of Aspects 1A or 4A-8A, wherein thesolvent comprises an aqueous solvent, organic solvent, or combination oforganic and aqueous solvent.

Aspect 10A is the composition of Aspect 2A or 3A, wherein the multi-armpolyethylene glycol terminated with thiol and/or the multi-armpolyethylene glycol terminated with a maleimide are dissolved in anaqueous solvent or combination of aqueous and organic solvent prior toforming the composition.

Aspect 11A is the composition of any of Aspects 1A-10A, wherein one ormore of the species is a polymer with a weight average molecular weight(M_(w)) or number-average molecular weight (M_(n)) ranging from about1,000 to 50,000 Daltons.

Aspect 12A is the composition of any of Aspects 1A-11A, wherein one ormore of the species is a polymer with a weight percent ranging fromabout 1 to 30% in solvent.

Aspect 13A is the composition of any of Aspects 1A-12A, wherein thespecies may be linear, Y-shaped, 3-arm, 4-arm, 6-arm, 8-arm, branched,block-co-polymer, random-co-polymer, or gradient-co-polymer.

Aspect 14A is the composition of any of Aspects1A-13A having a viscosityof less than or equal to 10 Pa*s.

Aspect 15A is the composition of any of Aspects 1A-14A having a pH inthe range of 3-11.

Aspect 16A is the composition of Aspects 2A, 3A, or 11A-15A, wherein themulti-arm polyethylene glycol terminated with thiol and/or the multi-armpolyethylene glycol terminated with a maleimide have a pH in the rangeof 3-11 when dissolved,

Aspect 17A is the composition of any of Aspects 1A-16A, wherein thecomposition has a storage modulus G′ ranging from 0.001 Pa to 20,000 Paat a temperature ranging from 20-160° C.

Aspect 18A is the composition of any of Aspects 1A-17A, wherein thecomposition has a gelation rate ranging from 0.1 seconds to 30 minutesat body temperature.

Aspect 19A is the composition of any of Aspects 1A-18A, wherein thecomposition has a mass percent swelling in the range of 0-1000%.

Aspect 20A is the composition of any of Aspects 1A-19A, wherein one ormore of the species is delivered at a volume in the range of 5 to 1000μL.

Aspect 21A is the composition of any of Aspects 1A-20A, wherein theimplantable network has a length in the range of 0.1 to 30 cm.

Aspect 22A is the composition of any of Aspects 1A-21A, wherein one ormore of the species includes one or more of a therapeutic agent, animaging agent (i.e. microbubbles), spermicide, antimicrobial,anti-inflammatory, antiviral, steroid, hormone, RNAi, protein, peptide,antibody, nucleic acid and/or fragment thereof, and/or vasodilator.

Aspect 23A is the composition any of Aspects 1A-22A, wherein theimplantable network is detectable by imaging modalities includingultrasound, MRI, CT, and/or X-ray.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings illustrate certain aspects of embodiments ofthe present invention, and should not be used to limit the invention.Together with the written description the drawings serve to explaincertain principles of the invention.

FIG. 1 is a schematic diagram showing an occlusive polymer device thatis implanted into a bodily lumen through a needle and then dissolvesinto an aqueous state upon exposure to a stimulus.

FIG. 2 is a schematic diagram showing a tightly-networked,stimuli-responsive hydrogel being exposed and reversed using light asthe stimulus.

FIG. 3 is a schematic diagram showing delivery of a stimulus to anocclusion in the lumen of the vas deferens according to embodiments ofthe invention.

FIG. 4 is a schematic diagram showing delivery of a stimulus to anocclusion in the lumen of a fallopian tube according to embodiments ofthe invention.

FIG. 5 is a schematic diagram showing a multi-lumen catheter as well asa cross-section of the multi-lumen catheter, which can deliver one ormore stimuli to an occlusion in the body lumen according to embodimentsof the invention.

FIG. 6 is a table showing the force necessary to inject and form astimulus-responsive device.

FIG. 7 is graph showing the rheological properties of astimulus-responsive device formed from two macromers.

FIG. 8 is a graph of NMR spectra showing degradation of a photolabilemoiety, o-nitrobenzyl ester (oN13), as a result of a 2 Joule exposure tolight using a fiber optic.

FIGS. 9A-9C are bar graphs showing reduction in G′ (storage modulus)(FIG. 9A), reduction in G″ (loss modulus) (FIG. 9B), and reduction in N(normal force) (FIG. 9C) for a stimuli-responsive hydrogel upon exposureto ultraviolet light over time (50 minutes).

FIG. 10 is a bar graph showing the metabolic activity of Leydig cellsafter exposure to different dosages of IJV light demonstrating thebiocompatibility of the UV-exposure on a male reproductive cell line.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to various exemplary embodiments ofthe invention. It is to be understood that the following discussion ofexemplary embodiments is not intended as a limitation on the invention.Rather, the following discussion is provided to give the reader a moredetailed understanding of certain aspects and features of the invention.

Polymeric Medical Devices and Methods of Reversal

The present invention, in embodiments, describes polymeric medicaldevices that are formulated in such a way that they are occlusive withina body lumen once implanted, but can be reversed upon command when anexternal stimulus is applied. Once reversal is performed, the devicedisintegrates, de-precipitates, dislodges, or dissolves, allowing forthe bodily duct to no longer be occluded. Examples of applications wherereversible occlusion can be utilized include reproductive tracts such asthe vas deferens and fallopian tubes, blood vessels, aneurysms, ducts,tumors, and organs. These reversible polymeric medical devices can alsoserve as effective sealants such as during surgery or tissue fillers oras wound care dressings or as drug-delivery devices. Examples ofreversal can include, but are not limited to, photodegradation (e.g.ultraviolet or infrared exposure), acoustic, and/or enzymaticdegradation.

In embodiments, the medical device, such as a polymeric medical device,can be in the form of an implant, hydrogel, gel, mesh, embolization,composition, or device (herein referred to interchangeably as animplant, hydrogel, gel, mesh, embolization, composition, device,occlusive device, occlusive composition, occlusive substance, or anyother applicable definition of gel, mesh, composition, device,formulation, or other object or article). In the context of thisdisclosure, the terms occlusion, occlusive, occlude, occluding and thelike refer to the act of occupying space and include but are not limitedto blocking, obstructing, disrupting, interfering with, or preventing,in whole or part, movement of a substance from one area to another. Inembodiments, the medical device, such as polymer gel, is implanted intothe vas deferens or fallopian tubes for male and female contraception,respectively, and can have the function of blocking or otherwiseinterfering with sperm or the oocyte from traveling within, through orinto the relevant tube(s), duct(s), and/or organ(s), thus causingtemporary or permanent infertility; preferably, temporary infertilitybecause the gel implantation can be reversed.

In one embodiment, the device is a hydrogel that is injected orimplanted into a vessel such as a reproductive organ (e.g. vas deferens,epididymis, uterus, or fallopian tube). The hydrogel is able to occludeor block the flow of cells (e.g. sperm cells or oocyte) resulting incontraception. The pores of the hydrogel are small such that they blockthe flow of the cells. The hydrogel may also be hydrophilic and swellsuch that fluid, carbohydrates, proteins (including antibodies), and/orother molecules may be able to travel through. In this manner, thehydrogel is a semi-permeable membrane.

In one embodiment, the hydrogel is formed by having one or moresubstances cross-link with each other such as macromers. The hydrogel isformed in situ. The hydrogel or its macromers can include componentsincluding, but not limited to, a polymer backbone, stimuli-responsivefunctional group(s), and functional groups that enable cross-linking.The functional groups that enable cross-linking can be end groups on themacromer(s).

The backbone can include one or more of natural or synthetic monomers,polymers or copolymers, biocompatible monomers, polymers or copolymers,polystyrene, neoprene, potyetherether 10 ketone (PEEK), carbonreinforced PEEK, polyphenylene, PAEK, polyphenylsulphone, polysulphone,PET, polyurethane, polyethylene, low-density polyethylene (LDPE), linearlow-density polyethylene (LLDPE), high-density polyethylene (HDPE),polypropylene, polyetherketoneetherketoneketone (PEKEKK), nylon,TEFLON®, TFE, polyethylene terephthalate (PETE), TEFLON® FEP, TEFLON®PFA, and/or polytnethylpentene (PMP) styrene maleic anhydride, styrenemaleic acid (SMA), polyurethane, silicone, polymeth rl methacrylate,polyacrylonitrile, poly (carbonate-urethane), poly (vin:_(s)7lacetate),nitrocellulose, cellulose acetate, urethane, urethane/carbonate,polylactic acid, polyacrylamide (PRAM), poly-(N-isopropylacrylamine)(PN1PAM), poly (vinylmethylether), poly (ethylene oxide), poly (ethyl(hydroxyethyl) cellulose), poly(2-ethyl oxazoline), polylactide (PLA),polyglycolide (PGA), poly(lactide-co-glycolide) PLGA,poly(e-caprolactone), polydiaoxanone, polyanhydride, trimethylenecarbonate, poly(β-hydroxybutyrate), poly(g-ethyl glutamate),poly(DTH-iminocarbonate), poly(bisphenol A iminocarbonate),poly(orthoester) (POE), polycyanoacrylate (PCA), polyphosphazene,polyethyleneoxide (PEO), polyethylene glycol (PEG) or any of itsderivatives including but not limited to, 4-arm PEG, 8-arm PEG, branchedPEG, or linear PEG, potyacryl acid (PAA), polyacrylonitrile (PAN),potyvinylacryl ate (PVA), polyvinylpyrrolidone (PVP), polyglycoliclactic acid (PGLA), poly(2-hydroxypropyl methacrylamide) (pHPMAm),poly(vinyl alcohol) (PVOH), PEG diacrylate (PEGDA), poly(hydroxyethylmethacrylate) (pHEMA), N-isopropylacrylamide (NRA), poly(vinyl alcohol)poly(acrylic acid) (PVOH-PAA), collagen, silk, fibrin, gelatin,hyaluron, cellulose, chitin, dextran, casein, albumin, ovalbumin,heparin sulfate, starch, agar, heparin, alginate, fibronectin, fibrin,keratin, pectin, elastin, ethylene vinyl acetate, ethylene vinyl alcohol(EVOH), polyethylene oxide, PLLA, PDMS, PIPA, PEVA, PILA, PEG styrene,Teflon RFE, FLPE, Teflon FEP, methyl palmitate, NIPA, polycarbonate,polyethersulfone, polycaprolactone, polymethyl methacrylate,polyisobutylene, nitrocellulose, medical grade silicone, celluloseacetate, cellulose acetate butyrate, polyacrylonitrile, PLCL, and/orchitosan.

In one embodiment, one or more of the tnacromers contains astimuli-responsive functional group. The functional group may be aphotolabile moiety. The photolabile moiety may be chosen based on thedesired photodegradation method such as ultraviolet (UV), near infraredlight (NIR), or infrared light (IR). The photolabile molecule issynthetically incorporated into the macromer through a linkage to aheteroatom such as oxygen, sulfur, or nitrogen or as an ether,thioether, thioester, ester, amide, or amine. Photolabi le moieties orgroups can include or can be synthesized from compounds including, butnot limited to, 2-nitrobenzyl, a-bromo-2-nitrotoluene, 2-nitrobenzylchloride, 5-methyl-2-nitrobenzyl alcohol, 5-hydroxy-2-nitrobenzylalcohol, 4,5-dimethoxy-2-nitrobenzyl alcohol,4,5-dimethoxy-2-nitrobenzyl chloroformate, 4,5-dimethoxy-2-nitrobenzylbromide, 5-chloro-2-nitrobenzyl alcohol ,5-tnethyl-2-nitrobenzylchloride, 4-chloro-2-nitrobenzyl alcohol, 2-nitrobenzyl alcohol,4-chloro-2-nitrobenzyl chloride, 4-fluoro-2nitrobenzyl bromide,5-fluoro-2-nitrobenzyl alcohol, and 2-methyl-3-nitrobenzyl alcohol,2-hydroxy-5-nitrobenzyl alcohol, 2-hydroxy-5-nitrobenzyl bromide,2-methoxy-5-nitrobenzyl bromide, 2-chloro-5-nitrobenzyl alcohol,2-fluoro-5-nitrobenzyl alcohol, 2-methyl-3-nitrobenzyl chloride, and2-acetoxy-5-nitrobenzyl chloride. In one embodiment, the photolabilemoiety is 4-[4-(1-Hydroxyethyl)-2-methoxy-5-nitrophenoxy]butanoic acid.The photolabile group can include, but is not limited to,a-carboxy-2-nitrobenzyl (CNB), 1-(2-nitrophenyl)ethyl (NPE),4,5-dimethoxy-2-nitrobenzyl (DMNB), 1-(4,5-dimethoxy-2-nitrophenyl)ethyl(DMNPE), 5-carboxymethoxy-2-nitrobenzyl (CMNB), nitrophenyl (NP), or anyof their derivatives. In another embodiment, the photolabile group isderived from benzoin, phenacyl, coumaryl, arylmethyl, thiopixyl, or arylsulfonami des. In another embodiment, a 1-o-phenylethyl ester,1-o-nitrophenylethyl, or any of their derivatives, is used as thephotolabile moiety. The 1-o-phenylethyl ester has an order of magnitudefaster degradation than o-nitrobenzyl ester, O-o-nitrobenzyl O′,O″-diethyl phosphate can also be used as the photolabile moiety.

Other examples of photolabile moieties include the nitrobenzylether-derived moiety described by A. Kloxin (see A. Kloxin et al,“Photodegradable hydrogels for dynamic tuning of physical and chemicalproperties”, Science. 2009 Apr 3; 324(5923): 59-63 and U.S. Pat. No.8,343,710, incorporated by reference in its entirety), as well as thosedescribed in U.S. Pat. No. 9,180,196, U.S. Patent ApplicationPublication Nos. US 20160153999 and 20120149781A1, and InternationalPatent Application Publication No. WO2015168090M, incorporated byreference herein in their entireties.

The structure of the photolabile moiety as well as the atom to which itis linked to affect the efficiency and wavelength required forphotodegradation. According to embodiments, the photolabile group islinked to the polymer backbone and/or the end-group through an amidebond. The amide bond prevents hydrolysis from occurring, and thus thedevice has a longer life span in vivo. According to embodiments, one,both, or all of the macromers contain a stimuli-responsive functionalgroup such as the photolabile moiety. The reversibility is quickest andmost efficient when both macromers contain a stimuli-responsivefunctional group. According to embodiments, one, both, or all of themacromers may contain multiple functional groups such as photolabilemoieties linked to each other. In one aspect, the reversibility isquickest and most efficient when multiple functional groups are used.

In one embodiment, the photolabile moiety is chosen based on factorssuch as its water solubility, decoupling rate, photolysis quantum yield,and the safety of its byproducts. For example, α-carboxy-2-nitrobenzyl(CNB) photolabile group has good water solubility, fast decoupling ratesin the microsecond range, high photolysis quantum yields (from 0.2-0.4)and biologically inert photolytic byproducts. The absorption maximum ofthis CNB group is near 260 nm, with photolysis still occurring atwavelengths as high as 360 nm. Therefore, light at wavelengths <360 nmcan be used for degradation purposes. Another example of a photolabilemoiety is the 1-(2 nitrophenyl) ethyl group. :It can be photolyzed atwavelengths of less than 360 nm. Other examples are1-4,5-dimethoxy-2-nitrophenyl) ethyl (DMNPE) and4,5-dimethoxy-2-nitrobenzyl (DMNB) which absorb and are photolyzed atlonger wavelengths (maximum occurring at 355 nm). In such cases, ratesof degradation can be lower than those obtained with the use of CNB orthe 1-(2 nitrophenyl) ethyl group as a photodegradable moiety. In theuse of 5-carboxymethoxy-2-nitrobenzyl (CMNB), a light absorbance maximumoccurs at 310 nm, while providing high levels of water solubility to thefunctional group. The nitrophenyl (NP) caging group is available on thecaged calcium reagent NP-EGTA (N6802), a photolabile Ca'' chelator thatcan be used to rapidly deliver a pulse of Ca²⁺ upon illumination withultraviolet light, with a high photolysis quantum yield of 0.23.

In one embodiment, the macromers contain functional groups that enablecrosslinking of the macromers to form the polymeric medical device.These functional groups are the end groups of the macromer(s). The endgroups cross link through a bioorthogonal reaction (sometimes referredto as “Click Chemistry”). A bioorthogonal reaction is utilized becauseit is highly efficient, has a quick gelation rate, occurs under mildconditions, and does not require a catalyst. One example of suchreaction is maleimide and thiol. Another type of Click reaction iscycloa.ddition, which can include a 1,3-dipolar cycloaddition orhetero-Di els-Alder cycloaddition or azide-alkyne cycloaddition. Thereaction can be a nucleophilic ring-opening. This includes openings ofstrained heterocyclic electrophiles including, but not limited to,aziridines, epoxides, cyclic sulfates, aziridinium ions, andepisulfonium ions. The reaction can involve carbonyl chemistry of thenon-aldol type including, but not limited to, the formation of ureas,thioureas, hydrazones, oxime ethers, amides, and aromatic heterocycles.The reaction can involve carbonyl chemistry of the aldol type. Thereaction can also involve forming carbon-carbon multiple bonds,epoxidations, aziridinations, dihydroxylations, sulfenyl halideadditions, nitrosyl halide additions, and Michael additions. Anotherexample of bioorthogonal chemistry is nitrone dipole cycloaddition. TheClick chemistry can include a norbornene cycloaddition, anoxanobornadiene cycloaddition, a tetrazine ligation, a [4+1]cycloaddition, a tetrazole chemistry, or a quadricyclane ligation. Otherend-groups include, but are not limited to, acrylic, cyrnene, aminoacids, amine, or acetyl. In one aspect, the end groups may enable areaction between the polymeric device and the cells lining the tube,duct, tissue, or organ that is being occluded.

In other embodiments, the polymeric device is formed by the successiveaddition of free-radical building blocks (i.e. radical polymerization).A radical initiator is formed which reacts with a monomer, convertingthe monomer into another radical, resulting in lengthening orpropagation of the polymer chain by successive addition of monomers.Non-limiting examples of polymers formed from radical polymerizationinclude polystyrene, poly(acrylic acid), poly(methacrylic acid),poly(ethyll methacrylate), poly(methyl methacrylate), poly(vinylacetate), poly(ethyleneterepthalate), polyethylene, polypropylene,polybutadiene, polyacrylonitrile, poly(vinyl chloride), poly(vinylidenechloride), poly(vinyl alcohol), polychloroprene, polyisoprene, vinylfluoride, vinylidene fluoride, trifluoroethylene,poly(methyl-α-chloracrylate), poly(inethylvinyl ketone),polymethacroleine, polyaurylmethacryate,poly(2-hydroxyethylmethamilate), poly(fumaronitrile),polychlorotrifluoroethylene, poly(acrylonitrile), polyacroleine,polyacenaphthylene, and branched polyethylene. The process of radicalpolymerization can be initiated by mechanisms including photolysis,thermal decomposition, redox reactions, and ionizing radiation. Thus, asolution of monomers can be delivered in situ to a body lumen, andpolymerization can be initiated by way of a device that delivers astimulus such as light, heat, ionizing radiation, or reagents thatinitiate redox reactions, to the monomers in situ to initiatepolymerization in the body lumen.

In one embodiment, the polymeric device is formed throughphotoinitiation. Wavelengths greater than 405 nm can be used to addcrosslinks and form the device. The same device that is formed throughphotoinitiation can be photoreversed as long as different wavelengthsare used to form and reverse the device.

In one embodiment, the components (e.g, monomers, macromers, orpolymers) that form the device have varied molecular weights, componentratios, concentrations/weight percents of the components in solvent, andcomposition of the solvent. Varying any, some, or all of theseproperties can affect the mechanical, chemical, or biological propertiesof the device. This includes properties such as, but not limited to,dissolution time, gelation rate/time, porosity, biocompatibility,hardness, elasticity, viscosity, swelling, fluid absorbance, meltingtemperature, degradation rate, density, reversal wavelength, reversaltime, reversal dosage, and echogenicity.

In embodiments, the polymer forms or dissolves within seconds, minutes,or hours, such as 1, 10, 20, 30, 50, 60 seconds; 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 15, 20, 25, 30, 40, 45, 50 or minutes; or 1, 2, 3, 4, 5, 6, 7, 8,9, or 10 hours or more. The rate of polymerization or depolymerizationwill depend on various factors such as compositions, component ratios,concentration/weight percentages, solvent composition, and other factorsas previously described.

In embodiments, the viscosity of the polymer solution ranges from about0.10 centipoise to about 100,000 centipoise, or any viscosity inbetween, including 0,1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300,400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, 6000, 7000,8000, 9000, 10000, 20000, 30000, 40000, 50000, 60000, 70000, 80000,90000, or 100,000 centipoise. In other embodiments, the viscosity of thepolymer solution ranges from about 1 to about 1,000 centipoise, or fromabout 1 to 7 Pa* s, such as from about 1 to 3 Pa*s. In otherembodiments, the viscosity of the polymer solution ranges from about 1to about 100 centipoise. By way of illustrative examples, a solution ofabout 1 centipoise has the viscosity of water, a solution in thehundreds of centipoise has the viscosity of motor oil, a solution ofabout 1000 centipoise has the viscosity of glycerin, and a solution ofabout 50,000 centipoise has the viscosity of ketchup. However, it ispreferred that the viscosity of the polymer solution is maintained lowenough so that it is not too viscous such that the injection cannot beperformed with a syringe and needle. The viscosity of the polymersolution can be manipulated by the varying the polymer and/or solventchosen, the polymer concentration, polymer molecular weight,crosslinking, or by the addition of additional agents includingmicrobubbles and carbon-based materials i.e. graphene.

In one embodiment, the molecular weight of the components can be variedfrom around 1 kD to 1,000,000 kD. The molecular weight of the polymer ispreferred to be from 10 kD to 80 kD. In one example, a high molecularweight can yield small pores in the device and thus, create an effectiveocclusion. A high molecular weight can also create a more viscoussolution and thus, can be more difficult to inject. In otherembodiments, the polymers can have a weight average molecular weight(M_(w)) or number-average molecular weight (M_(n)) ranging from about1,000 to 1,000,000 Daltons as measured by GPC (gel permeationchromatography) with polystyrene equivalents, mass spectrometry, orother appropriate methods. In embodiments, the number-average molecularweight (M_(n)) or the weight average molecular weight (M_(w)) ofpolymers of the invention can range from about 1,000 to about 1,000,000Daltons, such as from about 3,000 to about 60,000 Daltons, or from about20,000 to about 90,000 Daltons, or from about 150,000 to about 900,000Daltons, or from about 200,000 to about 750,000 Daltons, or from about250,000 to about 400,000 Daltons, or from about 300,000 to about 800,000Daltons, and so on. Further, the degree of polymerization of thepolymers in embodiments can range from 1 to 10,000, such as from 50 to500, or from 500 to 5,000, or from 1,000 to 3,000.

In embodiments, the chain length or degree of polymerization (DP) canhave an effect on the properties of the polymers. In the context of thisspecification, the degree of polymerization is the number of repeatingunits in the polymer molecule. In embodiments, the polymers include from2 to about 10,000 repeating units. Preferred are polymers which includefrom 5 to 10,000 repeating units, such as from 10 to 8,000, or from 15to 7,000, or from 20 to 6,000, or from 25 to 4,000, or from 30 to 3,000,or from 50 to 1,000, or from 75 to 500, or from 80 to 650, or from 95 to1,200, or from 250 to 2,000, or from 350 to 2,700, or from 400 to 2,200,or from 90 to 300, or from 100 to 200, or from 40 to 450, or from 35 to750, or from 60 to 1,500, or from 70 to 2,500, or from 110 to 3,500, orfrom 150 to 2,700, or from 2,800 to 5,000, and so on.

If two or more components are used to form the polymeric medical device,the ratio of the components can be varied. The ratio can be 1:1, 2:1,1:2, 3:1, 1:3, and so on, a 1:1 ratio allows for the highest degree ofcross-linking to occur. The ratio determines the rate of cross-linkingand thus, gelation of the device.

For occlusion or tissue fillers, the size of the needle or catheter canbe chosen based on the estimated size of the body lumen from theliterature, or determined by imaging the dimensions of the lumen of thesubject through ultrasound or other imaging modality. In embodiments,the size of the needle can be between 18 gauge to 34 gauge. In otherembodiments, the size of the needle is between 21 gauge and 31 gauge. Inother embodiments, the size of the needle is at least 23 gauge, such asbetween 23 gauge and 29 gauge. In another example, the needle that isused to deliver the injection solution contains bores on the side, whichallow for the solution to be excreted around the needle, in addition tothe bevel.

For sealant or coating applications, the device may be applied usingdifferent extrusion approaches, such as through needles, catheters,nozzles, spray applicators, and/or plastic tips. The applicator may bechosen based on factors such as desired application, tissue surfacearea, coating thickness, and gelation rate.

In one embodiment, the weight percent, or concentration of thecomponents in solution, is varied from around 1% to around 50% of thecomponent in solvent, such as from 1% to 2%, from 2% to 3%, from 3% to4%, from 4% to 5%, from 5% to 6%, from 6%, to 7%, from 7%, to 8%, from8% to 9%, from 9% to 10%, and so on. In another embodiment, the weightpercent of the macromer is from around 2.5% to around 20% in thesolvent, including 6% to around 20%, 7% to around 20%, 8% to around 20%,as so on. The weight percent can affect the mechanical and chemicalproperties of the polymer, such as increasing or decreasing pore size,viscosity, hardness, elasticity, density, and degradation.

The solvent that the component is dissolved in can be aqueous(water-based) or an organic solvent e.g. DMSO, PEG, ethanol. The finalcomposition contains excipients for purposes such as increasedsolubility. The pH of the composition in solution can be varied from 4to 9, such as from 4 to 5, 5 to 6, 6 to 7, 7 to 8, and 8 to 9. The pH ofthe solution can affect the gelation time and stability of the macrotnerin solution.

In one embodiment, the gelation rate and time of the polymer devicevaries. Gelation can occur instantaneously, in less than 1 minute, orwithin 1-10 minutes. In one embodiment, the device swells upon contactwith the fluids inside the body. Swelling allows for the device tosecure itself or “lock” within the lumen to form a good occlusion. Thedevice can swell greater than 100%, such as 100-200%, 200-300%,300-400%, and so on. The greater the device swells, the greater thelikelihood of the device allowing fluid to travel through, and forhydrostatic pressure to be reduced. Swelling may also allow for thedevice to properly secure itself within the body lumen.

According to another embodiment, the device includes pores. The poresare homogenous on the surface of the device. The porosity is defined bythe properties of the macromers and cross-linking of the macromers. Inembodiments, the pore diameter of the formed polymer ranges from 0.001nm to 3 μm, such as from 0.001 nm to 1 μm. In other embodiments, thepore diameter ranges from 0.01 nm to 100 nm, or from about 1 nm to about1 μm. In other embodiments, the pore diameter is 0.01, 0.02, 0.03, 0.04,0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40,0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70,75, 80, 95, 90, 95, or 100 nm. In other embodiments, the pore diameteris at least the size of an atom (0.5 nm). Specific pore sizes can betargeted to provide an optimum porosity that provides maximum flow offluid while blocking the flow of sperm cells or ova. In otherembodiments, the pores range from 0.1 nm to 2 microns in diameter. Inone embodiment, the device is suitable for occlusion of reproductivecells. The pores are less than 3 urn to prevent the flow of sperm. Thepores allow for fluid to travel through the hydrogel. The mesh size ofthe device is small enough to block reproductive cells from traversingthrough.

In embodiments, the length of occlusion produced in a body lumen as aresult of administering the occlusive substance ranges from 0.1-5centimeters in length, including 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8,0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1. 2.2,2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6,3.7, 3.8, 3.9, 4.0, 4.1, 42, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, and 5.0cm in length.

In one embodiment, the device does not degrade inside the body i.e. itis permanent. In another embodiment, the device degrades in the body viaan endogenous stimulus (e.g. hydrolysis). The degradation rate is slowenough that the device remains an effective occlusion inside the bodyfor greater than three months, such as 6 mos. or greater, such as 1-5years, in vivo. According to another embodiment, the device degradesupon application of an exogenous stimulus e.g. photodegradation (e.g.ultraviolet or infrared exposure), acoustic, and/or enzymaticdegradation.

In one embodiment, a multi-syringe system is used to inject or implantthe polymeric device for occlusion. Each syringe can inject a separatemacromer. The system can also contain a component that mixes themacromer solutions before implanting into the body and has multiplechannels that prevent the macromer components from mixing. The macromerscross-link in situ to form the occlusive device. In another aspect, thecross-linking is complete within the injection device prior to thedevice being implanted into the body. The injection speed and injectionvolume can be controlled. The injection device can be single use anddisposable, or can be multi-use with a replaceable cartridge containerin which the macromer solutions are delivered.

In one embodiment, a needle or catheter or combination of both can beused to implant the device into the body. For example, if implantinginto the vas deferens, a needle must first be used to puncture the thicklayers of smooth muscle. However, an angiocath or over-the-needlecatheter can also be used, which first punctures the vas deferens andthen replaces the needle with a catheter. This method can circumventproblems such as the needle puncturing the smooth muscle orextravasating the polymeric material past the lumen. If implanting thedevice into the fallopian tubes, then a catheter based approach must beused to access the tubes. The gauge of the needle and/or catheter can bechosen based on the maximum diameter of the lumen that is being occludedas well as the viscosity of the solutions being injected. For example,it is recommended that for vas deferens occlusion, a needle with a gaugehigher than 24g is used because the inner diameter of the vas deferensis 0.5 mm such as 25g, 26g, 27g, 28g, 29g, and 30g needles. In otherembodiments, the needle is extra extra thin walled (XXTW), extra thinwalled (XTW), thin walled (TW), or regular walled (RW). Standard needlesizes are readily available such as at http ://www. sigmaaldrich.comichemistrylstockroom-reagents/leaming-center;/technical-library/needle-gauge-chart.html.

If the device is used to occlude the vas deferens for malecontraception, the procedure can be performed surgically ornon-surgically. In the surgical method, the physician uses thetraditional vasectomy or no-scalpel vasectomy (NSV) technique. The vasdeferens is identified, isolated, and then exteriorized through a smallpuncture in the scrotal skin. Then, the device is injected or implantedonce the needle and/or catheter is inside the vas lumen.

Vas-occlusion can also be performed non-surgically such as throughpercutaneous injection, which may or may not be image-guided (e.g.ultrasound-guided). For example, once the vas deferens is isolated, anultrasound probe is placed on or near the vas to guide the percutaneousinjection. In some embodiments, the method further includes applyingultrasonic energy and visually identifying the vas-deferens by way ofultrasound imaging prior to, during, or after administering theocclusive substance. In some embodiments, the method further includesapplying ultrasonic energy and determining an inner (e.g lumen)diameter, outer diameter, and length of the vas deferens by way ofultrasound imaging prior to, during, or after administering theocclusive substance. In some embodiments, the method further includesapplying ultrasonic energy and identifying the lumen of the vas deferensby way of ultrasound imaging prior to, during, or after administeringthe occlusive substance. In some embodiments, the method furtherincludes applying ultrasonic energy and visually confirming placement ofa needle or catheter or a portion thereof into the lumen of thevas-deferens by way of ultrasound imaging prior to, during, or afteradministering the occlusive substance. In some embodiments, the methodfurther includes applying ultrasonic energy and visually confirmingplacement of the occlusive substance in the lumen of the vas deferens byway of ultrasound imaging. In some embodiments, when the occlusivesubstance is a polymer, the method further includes applying ultrasonicenergy and monitoring of polymerization of the echogenic vas-occlusivepolymer in real time by way of ultrasound imaging. In some embodiments,the method further includes determining one or more dimensions of anocclusion formed by the administered substance inside the lumen of thevas deferens by way of ultrasound imaging.

In embodiments, ultrasound is used to image the vas-deferens and thevas-occlusive polymer during and after placement inside the vasdeferens. Ultrasound based imaging is a painless and convenientdiagnostic method that functions by projecting sound waves into thebody, and then measuring the refraction, reflection, and absorptionproperties of the imaged-tissue to assess fine structure. Essentially,the way in which certain structures reflect sound waves allows for thegeneration of an image of the underlying organs and tissues. Forinstance, ultrasound imaging works best on mechanically more elastic,sound conducting tissues. Calcifications in the body (such as bone,plaques, and hardened tissues) provide degrees of acoustic impedancethat makes it difficult to image structures lying below them.

Ultrasound is an ideal candidate for imaging the tissues in the malereproductive system. First, ultrasound imaging is non-invasive and safe.There is no associated ionizing radiation produced with ultrasound asfound in X-Ray, PEI, and X-Ray imaging. Second, the male reproductivesystem, specifically the scrotum, does not contain bone, plaques, orhardened tissues which limit acoustic impedance. Finally, preparing apatient for ultrasound imaging is as simple as shaving the area ofinterest, cleaning the area of interest, applying anultrasound-conducting fluid interface gel to the surface of the skin,and applying the ultrasound probe in the correct orientation andposition. Therefore, ultrasounds are commonly found in urology clinicsand are used primarily for imaging the scrotum and penis.

Various frequencies can be used for imaging the vas deferens and/or gel,including contrast-pulse sequencing mode (7 MHZ), B-Mode imaging (14MHZ), and frequencies in between. Other possible ultrasound modes thatcan be used for the inventive methods include 2D mode, fusion, harmonicimaging (THI), color mode or color power angio, CW doppler mode, PWdoppler mode, M-Mode, anatomical M-mode (live or frozen image), B-Mode,color tissue doppler, PW tissue doppler, panoramic imaging, 3D/4Dimaging, and dual imaging. In some embodiments, the frequencies arebetween 1 and 20 MHZ, including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, or 20 MHZ. Additionally, the ultrasound canbe delivered at different intensities, such as between 0.1 to 1 W/cm²,including 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, and 1.0 W/cm².Additionally, the ultrasonic energy can be delivered at a specificpower, such as 0 to 20 Watts of energy, including 0, 0.1, 0.2, 0.3, 0.4,0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20 Watts. Additionally, the ultrasonic energy can bedelivered in pulsed or continuous mode. The ultrasound can be deliveredthrough an ultrasound unit. The ultrasound unit can be portable. Anexample of a portable ultrasound unit for scrotal imaging is the LOGIQV2, manufactured by GE Healthcare (Little Chalfont, United Kingdom).Another example of an ultrasound unit for scrotal imaging is theClearVue 350 by Philips (Amsterdam, Netherlands).

According to embodiments, various ultrasound probes or transducers areused for ultrasound imaging the vas deferens, including sector (phasedarray), linear and convex transducers. Ultrasound probes and theirselection have been discussed in the literature (see T. L. Szabo et al.,“Ultrasound Transducer Selection in Clinical Imaging Practice”, Journalof Ultrasound in Medicine, 2013, 32(4):573-582). Ultrasound transducersdiffer according to their piezoelectric crystal arrangement, physicaldimensions, shape, footprint (aperture), and operating frequency. It iswithin the ability of a skilled artisan (e.g. urologist or ultrasoundtechnician) to choose a transducer with appropriate characteristics toimage the area of the vas deferens that has been isolated. A hand-heldprobe can be chosen for imaging that is small enough to image the vaswithout interfering with other aspects of the procedure such asadministration of the occlusive substance.

Transducers are multi-frequency, meaning the frequency can be switchedelectronically between a range of frequencies (e.g. abdominaltransducers have 2-6 MHz). It is important for the user to select thehighest frequency which adequate depth of penetration for the anatomicarea of interest. In general, the higher the frequency of thetransducer, the greater than axial resolution and better the anatomicrepresentation of the image. However, there is a tradeoff betweenfrequency and depth of penetration. For imaging the testis, because ofthe close proximity of the organ to the surface of the skin, imaging canbe performed with high frequency transducers such as a linear arraytransducer of 12-18 MHz.

There are many factors that impact the image quality. Parameters andsettings can be modified by the user of the ultrasound in order toadjust and manipulate the image including: gain, time-gain compensation,frequency, depth/size, field of view, and cine function. A “good qualityimage” includes: (1) sufficient and uniform brightness, (2) is sharp andin focus, (3) adequate size, and (4) is oriented and labeled fordocumentation purposes. Furthermore, selection of a transducer iscritical for maximizing image quality. Linear array transducer probesproduce a rectangular image whereas a curved array transducer produces atrapezoidal shape. Linear array transducers are most commonly used inurology for imaging the testes and male genitalia. However, a curvedarray transducer can be helpful in visualizing both testessimultaneously.

In regards to safety, the FDA advises that the mechanical index (MI) andthermal index (TI) are kept below 1.90 and 6 degrees C., respectively.

According to embodiments, the non-surgical isolation of the vas deferensincludes use of the “three-finger technique” to isolate the vas deferensclose to the scrotal skin. According to other embodiments, thenon-surgical isolation of the vas deferens includes use of avas-fixation clamp to grip the vas deferens through the skin of thescrotum. In some embodiments, a combination of these techniques is used.Once isolated and secured beneath the scrotal skin, an occlusivesubstance such as a vas-occlusive polymer can be administered into thevas deferens by way of percutaneous injection or controlled intra-vasalinfusion.

According to some embodiments, the occlusive substance such as avas-occlusive polymer is innately echogenic. In some embodiments, thepolymer device is echogenic due to the presence of microbubbles presentin the polymer solution. In other embodiments, the polymer device isechogenic due to other constituents present in the polymer solution.

Embodiments of the invention additionally provide for the use ofultrasonic imaging to confirm placement of the occlusive substance intothe vas deferens lumen, determine location of the occlusion, one or moredimensions of the occlusion such as length and diameter, as well asmonitor the long-term stability of the occlusion in the vas deferens. Inanother embodiment, a saline-microbubble solution may be injected intothe body lumen and imaged to determine if the microbubbles are occludedby the polymer device. Thus, this ultrasound could be used to determineif an effective occlusion formed. These same embodiments can applysimilarly for occlusion of the fallopian tubes for female contraception.For example, the material to occlude the fallopian tubes can beechogenic and imaged using an ultrasound probe (e.g. transvaginalprobe).

When the patient requires or desires reversal of the occlusion, areversal procedure can be performed. Reversal can be performed usingultrasound, x-ray, infrared, thermal energy, magnetic, chemical,enzymatic, physical, vibrational, electric, mechanical stimuli, and/orlight. In one embodiment, reversal of the device is performed byexposing energy from an energy source, such as light, to the area wherethe device is implanted. Light sources include, but are not limited to,ultraviolet (UV), near infrared (NW), or infrared (LR) light. If thedevice includes photodegradable monomer(s) or macromer(s), then themonomer(s) or macromer(s) is cleaved and the device transitions from asolid to liquid state when exposed to light. If the monomer(s) ormacromer(s) serve a structural purpose, then the cleavage results inmechanical degradation of the device. The device can be designed to onlybe degraded at specific wavelengths of light or specific intensities oflight or a combination of both.

In one embodiment, the device is exposed to the light externally, inwhich case the reversal procedure is non-invasive and non-surgical. Thedevice can be exposed to light through a catheter or needle insertedinto the body lumen, in which case the procedure can be done surgically,non-surgically, or minimally invasively. Light delivering catheters areknown in the art, non-limiting examples of which include those describedin U.S. Pat. Nos. 7,252,677 and 7,396,354, which are incorporated hereinby reference. Further, the light delivering catheter can be capable ofdelivering both light and/or a solution having an agent that assists indissolving the device, flushing the device, etc. The catheter or needlecan assist in mechanically disrupting the device. If light is deliveredthrough a fiber optic, then the fiber optic can be sculpted to assist inmechanical or chemical reversal of the device. Thus, embodiments of thepresent invention include methods in which both light and/or a solutionand/or a mechanical action are used to reverse the device.

In one embodiment, exposure of the device to light takes place via anexternal light source. In such a case, bringing the polymer device andthe body lumen directly under the skin layers in a clinical settingprior to exposure can increase the penetration of the appropriate lightfrequencies to the appropriate depth to have the desired degradationeffect on the device. Light can be introduced directly to the body lumenand the device through a catheter or needle. The catheter or needle canbe inserted percutaneously under ultrasound-guidance. Ultrasound couldalso be used to determine if the reversal (e.g degradation, dissolution,or de-precipitation) was successful. The dissolution of the device canbe observed in real-time.

In one embodiment, the light can be exposed above the skin and penetratethe skin such that the photoreversible device is exposed. The light canhe ultraviolet (UV) or infrared (IR), although infrared (IR) light isable to penetrate skin deeper than ultraviolet (IR). Photodegradation ismost effective when the polymer device is most superficial to the skin.

Photoreversal can be accomplished with UV illumination using a UV laser,UV flashlamp, UV fluorescence microscope, or UV fiber optic. Alight-emitting diode (LED), violet diode lasers, or a 2-photon lightsource can be used.

In one embodiment, the ultraviolet light that is used has a definedwavelength. Various wavelengths can impact the degradation rate of thedevice. The UV wavelengths can range from 260 nm to 405 nm. In oneembodiment, the photolabile moiety is designed to detach from thepolymer in micro- to milli-seconds by flash photolysis, resulting in apulse (concentration jump) of the cleaved product when light is applied.There is a significant reduction in the storage modulus, loss modulus,or normal force of the occlusive device when exposed to light. Thus, thedevice is no longer able to effectively occlude the site. The structureof the photolabile monomer can be modified to allow attenuation ofcertain wavelengths of light and modification of absorbance properties.The concentration of the monomer can be modified to control lightabsorbance based on the molar absorptivity of the photolabile group atthe wavelength of interest.

Photodegradation can be accomplished with IR light, including but notlimited to, near-infrared, short-wavelength infrared, mid-wavelengthinfrared, long-wavelength infrared, or far-infrared. The wavelength ofthe infrared light can range from 700 nanometers to 1100 microns. Thefrequency of the infrared light can range from 300 GHz to 450 THz,

The occlusive device can contain gold nanorods (GNRs) for inducing aphotothermal effect. The occlusive device can contain graphene or any ofits derivatives for converting the infrared light into heat with highefficiency. The occlusive device can contain nanocrystals for inducing aphotothermal effect. In one embodiment, the occlusive device includesup-converting particles (UCNPs). UCNPs can convert low-energy and deeplypenetrating NIR to high-energy radiation, such as UV/visible/MR spectralrange through a phenomenon known as photon upconversion. Monotonic UCNPscan be synthesized in a controlled fashion with lanthanide (Ln³⁺) in thehost lattice. Other sensitizers such as trivalent Yb³⁺and Nd³⁺ions canbe activated by 980 nm and 800 nm light. Once activated, the conversionfrom NIR to UV light can cleave the photolabile moieties to causereversal of the device from within.

In one embodiment, reversibility is dependent upon light intensity. Thelight intensity can range from 0.1-40 mW/cm². It is preferred that alight intensity of less than 40J/cm², such as 5-20 MW/cm², is used.Light intensity can be flood-based (non-polarized light) or laser(polarized). Polarized laser light can allow for increased degradationwith lower light intensity due to tuning of the wavelength to a specificfrequency. Furthermore, lowered light intensity can contribute to alower degree of potentially adverse cellular effects. The light can becollimated, or can be partially shielded with an opaque photomask tocreate exposure gradients. The photomask can be moved at various ratese.g. 0.5, 1.2, 2.4 mm/min.

In one embodiment, the efficacy of the reversal is dependent uponexposure time of the hydrogel to light. Exposure time can range from 1second to 3,600 seconds. The exposure time is preferably from 1 secondto 1,200 seconds. In embodiments, the amount of time sufficient todegrade a particular occlusion sufficient to reverse the occlusiveeffect depends on the particular photodegradation protocol that is used,the composition of the occlusive material and its photolabile moieties,and the concentration of the photolabile moieties. The amount of timecan range for example from 10 seconds to 1 minute, up to 2 minutes, orup to 3 minutes, or up to 4 minutes, or up to 5 minutes, or up to 6minutes, or up to 7 minutes, or up to 8 minutes, or up to 9 minutes, orup to 10 minutes. In one embodiment, exposure takes place over thecourse of one or multiple clinical visits, with each exposure furtherdegrading the implanted material.

In one embodiment, reversal is expedited via the addition of otherexternal stimuli outside of the exposure of light from the UV spectrum.In one case, this can include addition of physical stimuli (e.g.ultrasound vibration, cavitation, physical manipulation, muscularstimulation, piercing of the occlusion with a needle, catheter, fiberoptic, drill, etc.) In one case, this can include the addition of asecondary chemical agent that degrades the occlusion via secondarychemical means such as enzymatic cleavage, reversal of the crosslinks,ionic solution, pH-altering solution, or addition of some other cleavagefactor.

Release of factors from within the device can occur upon exposure to thestimulus (e.g. ultraviolet or infrared light). These factors can includebut are not limited to: spermicidal agents, fertility agents, hormones,growth factors, anti-inflammatory drugs, anti-bacterial agents,anti-viral agents, adherent proteins, contrast agents, imaging agents,therapeutic drugs, antimicrobials, anti-inflammatories, spermicidalagents, vasodilators, steroids, ionic solutions, proteins, nucleicacids, antibodies, or fragments thereof. The factors can be releasedfrom the device through sustained-release. The patient can self-activatethe release of the factors from the device. The factors can be releasedduring an in-office visit to the physician using similar methods thatare used to reverse the device e.g. light.

In some embodiments, the reversal procedure involves one or moremodalities such as ultrasound, x-ray, infrared, thermal energy,magnetic, chemical, enzymatic, physical, vibrational, electric, ormechanical stimuli. Ultrasound can also be used to determine thelocation of the device in the body lumen, guide the stimulus to thelocation of the device, and/or determine if the reversal was successful(e.g. given that the device is partially, mostly, or completely nolonger visible on ultrasound). Further, as described below, ultrasoundcan be used directly to reverse the polymeric device. Any or all ofthese modalities can be used to modify the rate and degree ofdegradation. The use of multiple degradation strategies can allow for anincreased rate or increased ease of device dissociation.

According to one particular embodiment, a method of reversing anocclusion is provided. The method includes identifying a vessel of asubject in need of reversal of an occlusion; placing an ultrasound probeon or near the vessel and administering ultrasonic energy to image alumen portion of the vessel, and optionally under guidance of ultrasoundimaging, performing one or more or all of the following steps:identifying the occlusion in the vessel; percutaneously placing a needleor catheter or portion thereof into the lumen portion of the vessel;administering one or more stimulus into the lumen portion of the vesseltoward the occlusion; and/or confirming removal of the occlusion insidethe lumen portion as a result of administering the stimulus.

In one embodiment, ultrasound is applied at a particular frequency whichcauses the microbubbles in the polymeric device to vibrate. At aparticular threshold of intensity and/or frequency, the microbubbles canbe destroyed, which can cause a local shock wave, resulting incavitation and lysing of the device. Thus, the use of ultrasound canprovide a non-invasive method of reversing the occlusive provided by thedevice. Accordingly, one embodiment of the invention provides a methodof reversal of an occlusive device including applying ultrasonic energyto an occlusion at a frequency and/or intensity that is capable ofdestroying microbubbles inside the occlusion, thereby lysing anddestroying the occlusion.

In one embodiment, a level of ultrasonic energy needed for microbubblecavitation is determined. For example, a detector transducer receives ascattered level of ultrasonic energy, indicative of stable cavitation.Accordingly, a method for in vitro or ex vivo testing of microbubblecavitation is used to determine acoustic pressures necessary forreversal. For example, the gel with microbubbles is precipitated indialysis tubing or in an excised vas deferens or synthetic vas deferenstissue, and an ultrasound probe is applied at varying frequencies,wherein for each frequency, the amount of gel lost is measured. Once ameasurement is recorded which is expected to adequately reverse,de-precipitate, liquefy, dissolve, or flush out the polymer gel, such afrequency can be used to reverse, de-precipitate, liquefy, dissolve, orflush out the polymeric medical device in a subject.

Another embodiment of the invention is a method of reversing anocclusion, including: identifying a vessel of a subject in need ofreversal of an occlusion; placing at least one ultrasound probe on ornear the vessel and administering ultrasonic energy to image a lumenportion of the vessel, and optionally under guidance of ultrasoundimaging, performing one or more or all of the following steps:identifying an occlusion in the vessel; and/or administering focusedultrasonic energy at an intensity or frequency capable of breaking down,deteriorating, degrading, disintegrating, reversing, dissolving,destroying, removing, dislodging, de-precipitating, liquefying, flushingand/or reducing the occlusion in whole or part.

In one embodiment, the polymeric medical device is modified orcross-linked with fusion proteins, amino acid sequences, or peptides(natural or synthetic). The polymer can be modified with polyethyleneglycol (PEG), where PEGylation can enhance the bioconwatibility of thepolymer. The amino acid sequence can be cleaved with an endo- orexo-protease. The amino acid sequence can be a dipeptide or tripeptide.The addition of a protease causes the gel to de-precipitate, liquefy, ordissolve for reversal. The protease can occur naturally in the humanbody or can be an artificial protease. The amino acid sequence andprotease can be chosen from a database. The protease can be papain,bromelain, actinidin, ficin, or zingibain. In one embodiment, thedi-amino acid scission site can only be cleaved by a bacterial protease.Preferably, the protease is injected in a solution form into the body e:to reverse, de-precipitate, liquefy, dissolve, or flush out the polymerdevice.

According to another embodiment of the invention, a method of reversalof an occlusion of a body lumen, such as a reversal of vas occlusivecontraception, is provided. The methods of reversal includenon-surgically or surgically isolating the vas deferens andadministering a solvent into the vas deferens lumen. In embodiments, thesolvent is capable of deteriorating, breaking down, degrading,disintegrating, reversing, dissolving, destroying, removing, dislodging,dc-precipitating, liquefying, flushing and/or reducing, in whole orpart, an occlusion or mass, such as a vas-occlusive polymer occlusiondisposed in the lumen of the vas deferens. In some embodiments, themethod includes alternatively or in addition applying ultrasonic energyand visually identifying an echogenic polymer occlusion in the lumen ofthe vas-deferens by way of ultrasound imaging prior to, during, or afteradministering the solvent. In some embodiments, the method furtherincludes alternatively or in addition applying ultrasonic energy andvisually confirming placement of a needle or catheter or a portionthereof into the lumen of the vas-deferens by way of ultrasound imagingprior to, during, or after administering the solvent. In someembodiments, the method further includes alternatively or in additionapplying ultrasonic energy and visually confirming dissolution of theechogenic polymer occlusion disposed in the lumen of the vas deferens byway of ultrasound imaging, for example, during or after administeringthe solvent. In some embodiments, instead of administering a solvent,ultrasonic energy is applied at an intensity and/or frequency capable ofbreaking down the occlusion. For example, the ultrasonic energy can beapplied at an intensity and/or frequency that are capable of lysingmicrobubbles present in the occlusion, thereby breaking down theocclusion.

Another embodiment includes a method of removing an occlusion disposedin a body lumen, including: imaging a body lumen and an occlusiondisposed therein; and performing one or more or all of the following:applying a stimulus into the body lumen and allowing the stimulus todeteriorate, break down, degrade, disintegrate, reverse, dissolve,destroy, remove, dislodge, de-precipitate, liquefy, flush and/or reducethe occlusion in whole or part; and confirming deterioration of theocclusion by way of the imaging. The imaging can include any modality,including ultrasound, NMI, CT, x-ray, PET, PET-CT, or any combinationthereof

Apparatus for Delivering Stimuli

In embodiments, the present disclosure describes an apparatus that isable to deliver a stimulus or stimuli to change an implant disposed in abody, such as in a vessel lumen, body duct, tissue, interstitial space,or organ. Some of the embodiments described below focus on delivery ofelectromagnetic radiation (MR) and the impact of the delivered EMR onimplants, however, the ability to deliver other stimuli is included aswell.

In embodiments, the implant is a polymeric medical device, and anapparatus delivers a stimulus to change the properties of the implantsuch that it disintegrates, de-precipitates, dislodges, or dissolves.Examples of reversal mechanisms encompassed by stimuli delivered by theapparatus of the invention can include, but are not limited to,photodegradation (e.g. ultraviolet, visible, monochromatic, or infraredexposure), ultrasound, mechanical, electrical, physical, vibrational,magnetic, pH-based, temperature-based, ionic, reverse crosslinkingreactions (e.g. Click or bioorthogonal), and/or enzymatic degradation,and any combination thereof. In embodiments, the stimulus iselectromagnetic radiation, energy, sound waves, heat, vibrations,aqueous solutions (neutral, basic, or acidic), organic solvent,aqueous-organic mixture, enzymatic, protein(s), peptide(s), smallorganic molecules (<500 glmole), large organic molecules (> or =500glmole), nanoparticles, microparticles, quantum dots, carbon-basedmaterials, and/or any combination thereof.

In embodiments, the apparatus, system, and methods of the invention areused to change the properties of the implant within a bodily duct,lumen, vessel, tissue, intra-organ space, or organ. The hydrogel can beused to occlude the reproductive duct(s) of a mammal (e.g. vas deferensor fallopian tube) to cause contraception or sterilization. One resultof the change in properties of the implant after exposure to thestimulus is that the implant is no longer able to occlude the duct orvessel. In the case of contraception this change would restorefertility.

In embodiments, the apparatus is used to form an implant, or cure orpolymerize a hydrogel. The apparatus can deliver a stimulus to enableformation of the occlusive composition.

In embodiments, the apparatus includes components such as a powersource, a user interface, a catheter and/or needle, a fiber-coupledlight source, and/or an irrigation system, in a combination operable toremove an implant. In one embodiment, the apparatus includes an assemblywhich includes, but is not limited to, optical fibers, mechanicalholding and mounting hardware, and fused silica capillaries. Theassembly can vary with respect to the fiber or capillary type, fibersize e.g core, clad, buffer), overall assembly size, termination type(e.g. SMA, ST, shaped), end finish, numerical aperture of fiber, shapedend-tips, insertion loss, fiber anchoring (e.g. epoxy, crimp), a jacket,and bend diameters.

In one embodiment, power is supplied to the apparatus via 60V or 120V ACcurrent. However, embodiments of the device are compatible with othervoltages according to the single-phase voltage standard that is used inparticular countries or regions. In general, this can be in the range of100-127 volts or 220-240 volts. A representative list of single-phasevoltage standard by country can be found on the internet at the worldstandards website (seehttp://www.worldstandards.eu/electricity/plug-voltage-by-country/). Inone embodiment, the power is supplied to the device by a removable,rechargeable battery pack. In one embodiment, the device is chargedusing a charging dock. In one embodiment, the power is tunable.

In one embodiment, the user interface for the apparatus includes amechanism to advance and retract the stimuli introducing catheter. Theuser interface can include a dial, switch, or programmable interfacethat allows for modification of the magnitude of the stimulusintroduced. In one embodiment, this includes modification of the EMRintensity, including modification of the intensity, the Boolean state ofthe signal, the frequency of the pulses of the signal, and/or themodification of the wavelength of the EMR. In another embodiment, theuser interface allows for control of a flushing solution, including theBoolean state of the flush, the fluid flow rate of the flush, and/or thetype of solution being flushed.

In one embodiment, the hand-held catheterization apparatus includes aminiature camera at the tip of the device such as a fiber opticendoscope or fiberscope. The fiberscope, in conjunction with lightemitted from the catheterization device, provides capabilities forvisualization of the occlusion in situ on a display of the userinterface. In this embodiment, the catheterization device is advancedthrough the lumen until video on the display confirms that the devicehas reached the occlusion. Further, the fiberscope can confirm removalof the occlusion after one or more stimuli are provided through thecatheterization device.

In another embodiment, the hand-held catheterization apparatus includesa nanobot or other miniaturized tools such as drills, boring devices,rotating blades, lances, vibrating hammers, or any other tool capable ofdelivering a mechanical stimulus tethered to the end of the device thatis capable of physically removing portions of the occlusive deviceand/or breaking up the occlusion through mechanical stimuli. The devicecan have one or more tools which can be capable of grinding, sawing,piercing, boring, and/or drilling through the occlusion. The one or moretools can be controllable by way of the user interface.

In one embodiment, the user interface includes a computing device orinstrument that includes a processor (CPU), graphics processing unit(GPU), and non-transitory computer readable storage media such as RAMand a conventional hard drive, as well as a display. Other components ofthe computing device can include a database stored on the non-transitorycomputer readable storage media. As used in the context of thisspecification, a non-transitory computer-readable medium (or media) caninclude any kind of computer memory, including magnetic storage media,optical storage media, nonvolatile memory storage media, and volatilememory. Non-limiting examples of non-transitory computer-readablestorage media include floppy disks, magnetic tape, conventional harddisks, CD-ROM, DVD-ROM, BLU-RAY, Flash ROM, memory cards, opticaldrives, solid state drives, flash drives, erasable programmable readonly memory (EPROM), electrically erasable programmable read-only memory(EEPROM), non-volatile ROM, and RAM. The non-transitory computerreadable media can include a set of computer-executable instructions, orsoftware for implementing the methods, processes, operations, andalgorithms of the invention. The computer-readable instructions can beprogrammed in any suitable programming language, including JavaScript,C, C#, C++, Java, Python, Perl, Ruby, Swift, Visual Basic, and ObjectiveC.

In one embodiment, the apparatus includes a catheter or needle orcombination of both by which external stimuli can be introduced. Theexternal stimulus can be introduced subdermally, percutaneously, orintraluminally, to reverse the implant. The apparatus can include aneedle-sheathed catheter or a catheter-sheathed needle. The maximumneedle size/gauge is determined by the lumen of the vessel, duct, ororgan which will receive the external stimulus and as a result the exactsize of catheter, needle, or instrument is not critical so long as it isshaped and sized appropriately for a particular application. The gaugedneedle and/or catheter can have a diameter ranging for example between100 um and 5 mm, including 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 0.6mm, 0.7 mm, 0.8 mm, 0.9 mm, 1.0 mm, 1 mm, 2 mm, 3 mm, 4 mm, or 5 mm. Theneedle diameter is preferably between 0.3 mm to 1 mm. In embodiments,the size of the needle can be from 6 gauge to 34 gauge, such as from 10gauge to 34 gauge, or from 15 gauge to 32 gauge, or from 20 gauge to 26gauge, or from 22 gauge to 26 gauge, and so on. In other embodiments,the size of the needle is between 21 gauge and 31 gauge. In otherembodiments, the size of the needle is at least 23 gauge, such asbetween 23 gauge and 29 gauge. In other embodiments, the needle is extraextra thin walled (XXTW), extra thin walled (XTW), thin walled (TW), orregular walled (RW). Standard needle sizes are readily available such asathttp://www.sigmaaldrich.comichemistry/stockroom-reag,entslleaming-center/technical-library/needle-gauge-chart:Jinni.The needle system is used to introduce a secondary catheter within thelumen of the vessel. The needle or catheter can have a length between0.1 inch and 15 inches, preferably from 0.5 inch to 10 inches, such asfrom 0.8 to 5 inches, or from 0.4 to 1 or 2 or 3 inches. The needle canbe echogenic, or visible on ultrasound.

The needle or catheter system can include a single lumen. In oneembodiment, the needle or catheter remains within the body system duringstimulus exposure. In another embodiment, the needle or catheter isremoved from the body cavity after being utilized to introduce thestimuli within the body. In one embodiment, the needle or cathetersystem contains multiple lumen, which can be utilized to introducemultiple stimuli to the implant simultaneously or in a particularsequence. In another embodiment, the needle or catheter acts as a spaceholder to allow for the introduction of a secondary stimuli-introducingmechanism.

In one embodiment, the needle acts to introduce a multi-lumen catheterto the body system. In one embodiment, such a multi-lumen catheterincludes a single tubular system with multiple lumen running parallel toeach other. In another embodiment, such a multi-lumen catheter includesa nested series of catheters, in that the sheath and lumen of onetubular structure sits internal to another. Each lumen of catheter caninclude the same or a separate system for delivering a unique stimulusto the occlusive implantation. For example, each lumen of the multilumencatheter can include a fiber optic system, an irrigation system, afiberscope, or a miniature ultrasound probe. For example, the OlympusUM-2R, 12 MHz ultrasound probe, and UM-3R, 20 MHz probe, have an outerdiameter ofjust 2.5 mm (Olympus America Inc,, Center Valley, Pa.).

In one embodiment, the stimuli introducing component of the deviceincludes a fiber optic in isolation or in combination with anycombination of other stimuli.

In one embodiment, EMR is introduced within the body-system by way of afiber optic catheter. In such an embodiment, the fiber optic catheter iscoupled to an LED or other light source such as a laser that remainsexternal to the body system, contained within the device. The fiberoptic catheter is then introduced to the interior of the body system viaminimally invasive methods, allowing illumination of an implant.

In one embodiment, the fiber optic is advanced within the body-system bya secondary mechanical system or actuator. The fiber optic catheter canbe advanced and retracted by rotary motion, unpowered linear action, orpowered rotary or powered linear action. The fiber optic catheter can beadvanced and retracted according to commands introduced at the userinterface of the device.

In one embodiment, the fiber catheter includes layers of materials withvarying light-refracting properties. For example, the interior caninclude high -OH silica, while the sheathing can include low —OH silica.In embodiments, the silica is doped with materials to raise therefractive index (e.g. with GeO₂ or Al₂O₃) or to lower it (e.g, withfluorine or B₂O₃). (seehttps://www.rp-photonics.com/silica_frbers.html).

In one embodiment, the light emitting end of the fiber optic has avariety of sculpted tips that create different illumination patternsincluding, but not limited to, “up” taper, “down” taper, lens (convex),lens (concave), lens (spherical ball), diffuser, side-fire,ring-of-light, and angled end. Various sculpted tip shapes may be foundat http://w\vw.molex.com/mx upload/superfamitylpolymicro/pdfs/OpticalFiber Tips and Their Applications_Nov_2007.pdf. The fiber sculpted tipcan be chosen based on the application and type of implantation thatrequires exposure. The illumination pattern can have a shape orconfiguration that can be linear, circular, rectilinear, curvilinear,sideways, or can increase/decrease light divergence. In embodiments, thedevice is configured to emit circular or arced illumination patternsfrom 0-360 degrees or any range in between including from 15-90 degrees,30-180 degrees, 60-120 degrees, 90-240 degrees, 180-300 degrees, 45 to150 degrees, and so on.

In one embodiment, collimation or coupling components are used toprovide a stable platform for coupling light into and out of FC/PC,FC/APC, SMA, LC/PC, SC/PC, and ST/PC terminated fibers. The collimationor coupling component can be fixed or adjustable. The collimation orcoupling component directs a laser beam from the end of the fiber whilemaintaining diffraction-limited performance at the desired wavelength.

In one embodiment, the fiber-coupled LED includes a single LED that iscoupled to the optical fiber using the butt-coupling technique. Theoptical fiber can have a diameter that can be between 1 and 1000microns, or more preferably between 200 and 500 microns, such as from 1micron to 750 microns, or from 10 microns to 350 microns, or from 50microns to 150 microns, or from 100 microns to 480 microns, and so on.The optical fiber can also have a diameter in the millimeter range, suchas from 1-10 mm, 1-8 mm, 1-5 mm, 2-4 mm, or 2-3 mm for example forarterial or ductal applications. One of skill in the art will know howto upsize or downsize the instrumentation for a particular application.

In one embodiment, two or more, such as more than two, optical fibersare used. The bundle of optical fibers can be used to increase the lightintensity. The bundle of optical fibers can have a total diameterbetween 1000 microns to 10 mm. For instance, for an artery, the totaloptical fiber or fiber bundle diameter can be between 1 mm to 2 mm for apenile artery, 3 mm to 4 mm for a coronary artery, 5 mm to 7 mm for acarotid artery, and 6 mm to 8 mm for a femoral artery. Similarly, thetotal optical fiber bundle diameter can be between 2 mm to 4 mm for ahepatic duct, and 1 mm to 3 mm for a pancreatic duct. Thus, the totaloptical fiber or fiber bundle diameter can be adjusted according to theparticular clinical application (e g , the target vessel in which onewishes to remove an occlusion). Each fiber optic can be run through adifferent lumen of the catheter or needle system. The fiber optics canbe joined or fused together to run in parallel through a single lumen,or bundles fibers can run in parallel in one or more lumens of amulti-lumen catheter.

The coupling efficiency can be dependent on the core diameter andnumerical aperture of the connected fiber. The LED can be mounted to aheat sink. A high-powered LED properly mounted to a heat sink exhibitsbetter thermal management over time than an LED without a heat sink. TheLED can emit light in the following colors: red, green, blue, amber,violet, warm white, cool white, ultra-violet. The LED can be mounted toprinted circuit boards using surface-mount technology (SMT), also knownas a surface-mounted device (SMD).

The LED can be high-power and high-current. The LED can also include alow or high thermal resistant material. For high-power, high-currentLEDs, a low thermal resistant material is preferred. The forward voltage(V) of the LED can be from 0 to 5 V, such as from 0 to 1 V 1 V-2 V, 2V-3V, 3V-4V, or 4V-5V. The forward current (I_(F)) of the LED can befrom 0 to 2,000 mA, such as from 200 to 400 mA., 400 to 600 tnA, 600 to800 mA, 800 to 1,000 tnA, 1,000 to 1,200 mA, 1,200 to 1,400 mA, 1,400 to1,600 mA, 1,600 to 1,800 mA., and 1,800 to 2,000 mA. The modulationfrequency of the LED can be in the range of 1000 Hz and 3000 Hz,including 1100 Hz, 1200 Hz, 1300 Hz, 1400 Hz, 1500 Hz, 1600 Hz, 1700 Hz,1800 Hz, 1900 Hz, 2000 Hz, 2100 Hz, 2200 Hz, 2300 Hz, 2400 Hz, 2500 Hz,2600 Hz, 2700 Hz, 2800 Hz, 2900 Hz, or within any range encompassing anyof these values such as from 1,600 Hz to 2400 Hz, 1400 Hz to 2500 Hz,1700 Hz to 2300 Hz, 1100 Hz to 1900 Hz, 1400 Hz to 1600 Hz, 2300 Hz to2600 Hz, and so on. The modulation shape of the LED can be varied aswell such as triangle, single, or square.

Light emitting diodes have a divergent light emission, with radiancedegrading from the center of the cone of irradiation. Optical fiberexhibits a narrow angle of acceptance, predicted as falling betweentwelve and twenty degrees to normal. Efficiency of the coupling then canbe greatly improved by including a lensing system between the fiberoptic and the LED.

In one embodiment, the fiber coupled LED involves a system of lensing toincrease the coupling efficiency of the system. Such as system caninclude a microlens, a larger optical lens, or any combinatorial lensingsystem to more efficiently target the .LEDs radiant energy to the fiberacceptance cone.

In one embodiment, the apparatus emits short wavelength electromagneticradiation. The wavelength can range from 10⁻⁶nm (gamma) to 2,500 nm(deep violet). The wavelength can range from 365 nm to 405 nm, or from405 nm to 1000 nm, or from 200 nm to 2,500 nm, or from 250 nm to 450 nm,or from 300 nm to 425 nm, or from 330 nm to 420 nm, or from 350 nm to390 nm, or from 365 nm to 405 nm, or from 330 and 460 nm, or from 370 nmto 440 nm, or from 405 nm to 500 nm, or from 500 nm to 800 nm, or from700 nm to 2,500 nm or from 1000 nm to 10⁵ m. The wavelength emitted candepend on the implantation and the wavelength required for theimplantation to be stimulated. For example, the implant can be modifiedusing wavelengths between 300 nm and 500 nm, such as from 300 nm to 450nm, or from 200 nm to 410 nm, or from 250 nm to 350 nm, or from 320 nmto 380 nm, or from 280 nm to 405 nm, or more preferably, between 365 nmand 405 nm, or at any range recited herein.

In embodiments, the apparatus includes a UV lamp coupled with theoptical fiber. The UV lamp can emit light in UV-A, UV-B, or UV-C bands.In other embodiments, the apparatus includes an infrared lamp coupledwith the optical fiber. In other embodiments, the apparatus includes avisible lamp or LED coupled with the optical fiber. In otherembodiments, the apparatus includes a laser coupled with the opticalfiber. The laser can be chosen to emit a wavelength from ultraviolet tovisible to infrared. Non-limiting categories of laser sources includesolid-state lasers, gas lasers, excimer lasers, dye lasers, andsemiconductor lasers. An excimer laser is a non-limiting example of alaser emitting at ultraviolet frequencies, while a CO₂ . laser is anon-limiting example of a laser emitting at infrared frequencies. Thechoice of the laser will depend on the particular wavelength of lightemitted and its relative absorption by the occlusive device. In oneembodiment, the laser is a tunable laser which allows adjustment of theoutput wavelength. Descriptions of various laser sources are availablein the art including Thyagarajan, K., Ghatak, ?joy, Lasers: Fundamentalsand Applications, Springer US, 2011, ISBN-13:9781441964410, incorporatedby reference herein, as well as The Encyclopedia of Laser Physics andTechnology (available online athttps://www.rp-photonics.com/encyclopedia.html).

Various other sources of EMR wavelengths are known. For example, forgamma rays, radioactive sources such as ¹⁹²Ir, ⁶⁰Co or ¹³⁷Cs are used.For X-rays, an X-ray source such as an X-ray tube is used in conjunctionwith a collimator and a filter.

Additionally, the device can include a probe that emits radiofrequencywaves or microwaves, which are converted to heat in situ. For example,the device can include a miniature radiofrequency probe. The probe emitsradiofrequency radiation which results in both resistive and conductiveheating of tissue in contact with the probe. In embodiments of methodsof this disclosure, the probe can contact the occlusion itself, whichcan result in resistive and conductive heating of the occlusion.Alternatively, or in addition, the device can include a miniaturized tipthat heats through electrical resistance to provide thermal energy tothe occlusion. In embodiments, the needle and/or catheter can providefor cooling. In other embodiments, the miniaturized tip is configured tovibrate at selected frequencies. The occlusion can be chemicallyformulated such that it dissolves upon heating or vibrational energy.

In one embodiment, the apparatus is capable of introducing a particularenergy level of EMR to the implantation. The light intensity can rangefrom 0.1-40J/cm² such as from 0.1-1J/cm², 1-5J/cm², 5-10J/cm², 10-15J/cm², 15-20J/cm², 20-25J/cm², 25-30J/cm², 30-35J/cm², or 35-40 J/cm².It is preferred that less than 40 J/cm² of light intensity is used forin vivo applications.

The light intensity can be flood based (non-polarized light) or laser(polarized). Polarized laser light can allow for increased degradationwith lower light intensity due to tuning of the wavelength to thespecific frequency that interacts with the photolabile groups in thepolymers of the implant. Furthermore, lowered light intensity cancontribute to a lower degree of potentially adverse cellular effects.The EMR such as UV light can be collimated or can be partially shieldedwith an opaque photomask to create exposure gradients. The photomask canbe moved at various rates including 0.5, 1.2, 2.4 mm/min. Further, thefrequency of the light stimulus can be varied. For example, ultravioletlight has frequencies that range from 8×10¹⁴ Hz to 3×10¹⁶ Hz. Ifinfrared light is used, the frequency can range from 300 GHz to 450 THz.The light stimulus can also be provided in pulses.

In one embodiment, methods of the invention include introducing theneedle or catheter into the lumen of a bodily duct, vessel, tissue,interstitial space, or organ containing the implantation. The vessel canfirst be punctured using a hypodermic needle and then a single lumencatheter or multi-lumen catheter can be inserted into the area of theimplanted device, such as for example into, onto, near, or surroundingthe occlusive device or implant. Then, a stimulus such as EMR can beintroduced through the catheter or needle, For example, thelight-conducting fiber can be introduced through the catheter or needlesuch that the fiber optic is able to be extended into the lumen of thevessel or cavity containing the implantation and is able to apply lightonto the surface of the implantation, the side of the implantation, oris able to penetrate the implantation to apply light from within. Themethods can include touching the implantation or not when deliveringlight. In one embodiment, the needle and/or light-conducting fiberpunctures or enters the composition then delivers light, such asdelivering 360 degrees of light (around the needle or catheter) withinthe lumen to treat the composition disposed therein. This is especiallyuseful for implantations that are soft materials, such as hydrogels. Theillumination pattern can be varied to treat only part of the occlusivedevice and/or to administer light/energy from only part of the needle orcatheter. For example, the device can include an adjustable sheath orother structure for blocking or insulating the light/energy in a mannersuch that light/energy can be emitted from the device and/oradministered to an occlusive device from 5-180 degrees, or from 10-165degrees, or from 20-135 degrees, or from 30-110 degrees, or from 45-150degrees, or from 50-95 degrees, or from 55-85 degrees, or from 75-120degrees, or from 60-110 degrees, and so on, or any range of amountdisclosed herein, around an axis running lengthwise through theneedle/catheter.

In one embodiment, the exposure time of the stimulus can be seconds,minutes, or hours, but is preferably from 1 second to 20 minutes. Theimplantation can be removed, impacted, or reversed by the apparatuswithin seconds, minutes, or hours. In embodiments, the amount of timesufficient to degrade a particular polymer occlusion will depend on theparticular polymer make-up/chemistry, degradation protocol, and stimulithat are used, and can range for example from 10 seconds to 1 minute, upto 2 minutes, or up to 3 minutes, or up to 4 minutes, or up to 5minutes, or up to 6 minutes, or up to 7 minutes, or up to 8 minutes, orup to 9 minutes, up to 10 minutes, up to 20 minutes, up to 30 minutes,up to 60 minutes, up to 1 hour, up to 2 hours, up to 5 hours, up to 10hours, or up to 12 hours, or longer. The use of multiple stimuli fordegradation can result in shorter exposure times that are effective indegrading the polymer occlusion. In one embodiment, exposure takes placeover the course of one or multiple clinical visits, with each exposurefurther degrading the implanted polymer. The time exposure can also beperformed over the course of multiple treatments for the same or varyingamounts of time. For example, the stimulus can be applied once or moreper selected time period, such as per second, minute, hour, day, week oryear. For example, the treatment can be applied for a selected amount oftime at a selected interval from the time periods and intervals providedabove, or for any amount of time or time period or combination thereof.

In one embodiment, the apparatus can be configured to introduce a fluidthat is capable of acting on the implantation. The administered fluidcan be capable of changing the charge or pH of the environment which theimplantation is situated and/or reverse, dissolve, dislodge, orde-precipitate the implantation or assist in removing the reversed,dislodged, dissolved, or de-precipitated implant from the body. Inembodiments, the fluid is capable of deteriorating, breaking down,degrading, disintegrating, reversing, dissolving, destroying, removing,dislodging, de-precipitating, liquefying, flushing and/or reducing, inwhole or part, the occlusive implantation.

The fluid can be saline, phosphate-buffered saline, Ringer's solution,or a buffered solution, or any other non-toxic solutions or solvents.The fluid can be pressurized. The fluid can contain various buffedngagents including citrate, phosphate, acetate, or carbonate formaintaining the pH of the solution. For example, the solutions caninclude sodium or potassium bicarbonate for maintaining a basic pH. Thesolution can have a pH from 8-9, a of 7 (neutral), or a pH from 6-7.According to embodiments, the occlusive implantation is sensitive tochanges in pH such that acidic and/or basic stimuli result indepolymerization of the implant. Further, the fluid can contain one ormore agents (chemical or biological, as described below) to act on theimplantation and result in dissolution or depolymerization. In addition,the fluid can be or include various organic solvents such as DMSO, orother organic solvents, that are capable of dissolving the polymer ofthe occlusive implant.

Included in embodiments of the irrigation system is a fluid source suchas an IV bag of saline or another solution, an infusion pump such as aHarvard pump capable of being programmed to deliver the fluid throughthe catheter at a specific rate, and medical tubing such as polyethylenetubing connected to the irrigation system in the catheter. The infusionpump can be programmed to deliver the solution through the catheter at aconstant level or in pulses or bursts that exert physical pressure onthe occlusion. However, the infusion pump can also be programmed tolimit the volume of fluid so that the vessel, duct, or organ does notrupture during administration.

In one embodiment, the apparatus includes a multi-lumen catheter orneedle such that two or more different stimuli can be introducedsimultaneously. The stimuli can include, but are not limited to,electromagnetic radiation, chemical agent, biological agent (e.g. anenzyme) mechanical stimulus, or irrigation e.g. saline or anothersolution. For example, the chemical agent can be one that reverses apolymer synthesized by Click Chemistry (see David A. Fulton, “Synthesis:Click chemistry gets reversible” Nature Chemistry 8, 899-900 (2016)).The chemical agent can also be a reducing agent such as glutathionewhich breaks the cross-links of the hydrogel. The biological agent canbe a protease such as papain, bromelain, actinidin, ficin, or zingibainthat reverses the gel by digesting fusion proteins, amino acidsequences, or peptides (natural or synthetic) that are cross-linked tothe hydrogel. The chemical or biological agent can be delivered in asolution. The stimuli can be delivered in any combination such that eachindividual stimulus is delivered through a separate lumen of thecatheter.

In one embodiment, the apparatus includes a single handheld unit, inwhich all systems and subsystems are contained. In one embodiment, theapparatus includes a handheld unit in which all systems which come incontact with a patient are disposable. In such an embodiment, disposablecomponents can include but are not limited to the piercing needle, asection of fiber optic catheter, and a threaded connection head. Anexample of a hand-held unit is the Uro-C Cystoscopic System (seehttps://www.urosee.coml).

In another embodiment, the apparatus includes a non-consumable part(handle) with a consumable catheter/needle. In another embodiment, theapparatus is completely consumable using a built-in battery. As usedherein, “consumable” is intended to mean its commercial sense, i.e.intended to be used and replaced.

In another embodiment, the power supply and a portion of the userinterface are contained within a table mounted box. Power can be thentransmitted to the handheld portion of the apparatus, which can includea LED light source, further user interface components, and a couplingpoint to the disposable catheter/fiber head.

In any such embodiment of the apparatus, the apparatus includes asubsystem that allows for the introduction of a fluid flush through thestimuli introducing catheter system. A fluid reservoir can be containedwithin the device itself, or the system can include a port to allow forthe introduction of a fluid flush via a secondary syringe introductionsystem.

In one embodiment, the apparatus includes a disposable system, ith allsubsystems being contained in one handheld package.

In one embodiment, the apparatus includes a mechanical system, chemicalsystem, and/ or electromagnetic system to remove an implantation. Theapparatus can include any number of types of systems or combination ofsystems to remove an implantation from the body by causing a physical orchemical effect on an implantation.

In embodiments, methods for removal of the implantation are guided byultrasound. In particular, ultrasound can be used to guide placement ofthe catheter into the lumen of the vessel containing the occlusion. Forexample, ultrasound can be used to identify the lumen of the vessel,such as a vas deferens or fallopian tube, as well as image a needle thatcan be used to introduce a catheter into the vessel. Further, theimplantation can be imaged using a medical imaging modality prior tousing the apparatus, such as ultrasound, MRI, CT, x-ray, PET, PET-CT, orany combination thereof. The imaging can be used to determine thelocation, occlusive nature, length of the implant, or a combinationthereof.

An additional embodiment of the invention includes a method of reversalof an occlusion including non-surgically or surgically isolating theoccluded vessel and administering a solvent or solution in the lumen ofthe vessel that is capable of dissolving the occlusion. For example, themethod of reversal can rely on ultrasonic imaging to determine thelocation of the occlusion in the vessel. Then, the vessel such as a vasdeferens can be isolated. Then, a solvent or solution which is capableof dissolving the occlusion can be administered into the lumen of thevessel. Alternatively, the solvent or solution can be used to “flushout” the occlusion. For example, the solvents can include DMSO and thesolutions can include sodium or potassium bicarbonate. The solution canhave a pH from 8-9, 7-8, 7 (neutral), or 6-7. As an alternative tobicarbonates, other alkaline solutions can be used. Anywhere from0.01-20 cc of active agent, such as a solvent or solution, can beinjected into the lumen of the vas deferens, such as from about 0.01 ccto 0.02 cc, 0.02 to 0.03 cc, 0.03 cc to 0.04 cc, 0.1 cc to 20 cc, 0.2 ccto 15 cc, 0.05 cc to 10 cc, 0.05 cc to zi cc, or from 0.15 cc to 3cc,0.2 cc to 0.5 cc, 0.5 cc to 8 cc, and so on, or any range or amountbased on these values. However, the rate and volume of injections arelimited such that the injection force does not rupture the walls of thevessel. The dissolution of the polymer occlusion can then be monitoredin real time using ultrasound. Absence of the occlusion and patency ofthe vessel lumen can be confirmed via ultrasound imaging. Further, inthe case of removal of the occlusive device from the vas deferens,removal of the polymer occlusion can be confirmed through sperm countsand motility testing of ejaculates.

The apparatus can be a handheld device with a screen similar to acystoscope. The handheld device can be configured so that a user canpush a button to release or extend the optical fiber. Alternatively, theapparatus can shine light above the skin to degrade the implant, such asan otoscope or dental curing device.

The apparatus of the invention has several applications or industrialuses, including male and female contraception, occlusion of any organ,tissue, duct, etc. and/or reversal thereof; occlusion of artery to causenecrosis of tumor and/or reversal thereof; occlusion of aneurysm and/orreversal thereof; sustained release of factors, proteins, stem cells,drugs, antibodies, fertility boosting reagents, antibiotics,microbubbles, liposomes, or nanoparticles.

EXAMPLES Example 1 Dissolution of an Occlusive Polymer Hydrogel

FIG. 1 is a representation of an occlusive polymer device that isimplanted into a bodily lumen through a needle. The injection forms asturdy hydrogel that secures itself in the lumen. The hydrogel alsocontains pores on its surface, which are able to block the flow ofcertain cells, such as sperm for male contraception, or oocytes forfemale contraception. When the hydrogel is exposed to a stimulus (inthis case, the stimulus is in the form of a solution), the hydrogeldissolves into an aqueous state. Thus, the hydrogel no longer occludesthe bodily duct.

Example 2 Reversal of Hydrogel Upon Exposure to Light

FIG. 2 represents a tightly-networked, stimuli-responsive hydrogel beingexposed and reversed using light as the stimulus. In this case, thehydrogel is formed from two “star” (4-arm) macromers. Both macromerscontain photolabile moieties, which are photocleavable and provide thefinal hydrogel the ability to be reversed using light. The twoma.cromers form the hydrogel by having their end-groups cross-linkthrough a covalent reaction, such as a bioorthogonal reaction. In thefigure, a needle containing a fiber optic is depicted approaching thehydrogel. The fiber optic is emitting light in the visible spectrum,particularly violet. Upon exposure to the light, the photolabile groupswithin the hydrogel are cleaving and thus, the hydrogel is becomingirreversibly dissolved. Upon cleavage of the tight-network, thehydrogel's mechanical properties become reduced (e.g. storage modulus,loss modulus, normal force).

Example 3 Delivery of Stimulus to a Vas-Occlusive Device

FIG. 3 is a schematic diagram showing delivery of a stimulus to anocclusion in the lumen of the vas deferens through a percutaneousmethod. Ultrasound may also be used to assist in imaging the vasdeferens and guiding the percutaneous injection. Alternatively, the vasdeferens can be exteriorized through a small puncture in the scrotum,and then the stimulus can be exposed to the occlusion using a needle orover-the-needle catheter.

Example 4 Delivery of Stimulus to Fallopian Tube Occlusion

FIG. 4 is a schematic diagram showing an embodiment in which a stimulusis delivered to an occlusion in the lumen of a body, such as an oviduct,through a device of the invention, such as a catheter device. Accordingto embodiments, any stimulus according to those described herein may bedelivered. Delivery of the stimulus has an effect on the occlusion todisintegrate, de-precipitate, dislodge, and/or dissolve the occlusion,thereby reversing or otherwise interfering with functionality of theocclusion and the contraception produced by the occlusion.

Example 5 Delivery of Multiple Stimuli using a Multi-lumen Catheter

FIG. 5 is a schematic diagram showing a catheter device as well as across-section of the device. The diagram shows a catheter with multiplelumens, such as two lumens (in this case formed by a wall bisecting thecatheter), where one lumen allows passage of a stimulus-deliveringdevice such a fiber optic or bundle of fiber optics and another lumenallows passage or delivery of a fluid stimulus such as an enzymaticsolution, pH solution, or saline flush. It is also possible for thelumens of the catheter to deliver fiber optics of different wavelengths.It should be noted that a combination of fiber optics with differentwavelengths of light and/or 2 or more solutions may be delivered usingthe multi-lumen catheter.

Example 6 Injectability of a Stimuli-Responsive Material

The table in FIG. 6 demonstrates the force necessary to inject and forma stimulus-responsive device, as described in this disclosure. Twostimulus-responsive macromers (i.e. components I and 2) both containinga PEG-backbone, a photolabile moiety, and cross-link enabling end-groupswere synthesized, dissolved in aqueous solutions, and 100 of eachsolution was loaded into respective 1-mL syringes. The syringes wereassembled into a dual-barrel injection system. The system allowed forthe macromers to mix in a 25g needle, which is optimal for occludingbodily ducts such as the vas deferens. Next, the dual-barrel injectionsystem was placed into the dynamometer, which pressed on the plungers ata speed of 6.75 in/min. Data collection was stopped when the plungersreached the end of the syringe barrels. The table demonstrates thataround 6 lbf was required to inject components 1 and 2 through thissystem and needle, which is far below the set design criteria (10 lbf).

Example 7 Determining the Device's Mechanical Properties and Mesh Size

The rheological graph in FIG. 7 is a time sweep experiment of anocclusive hydrogel material formed from two macromers, as described inthis disclosure. This particular hydrogel formulation has a mean G′(storage modulus) of 668.5 Pa and a mean G″ (loss modulus) of 21.66 Pa.The mesh size can be calculated through the following formula:

$G_{p} \approx \frac{kT}{\xi^{3}}$

From the equation, it is determined that the mesh size for this hydrogelsystem ranges from 17 to 18.5 nm, Thus, this hydrogel would be aneffective occlusion if its purpose was to block reproductive cells;sperm have a diameter of 3-5 um and oocytes have a diameter of 3-8 mm.In comparison, most proteins would he able to traverse through thishydrogel's mesh size (myoglobin=3.5 nm, hemoglobin=5.5 nm; BSA=2 nm;IgG=8 nm; IgM=19 nm).

Example 8 Transformation of a Photolabile Molecule

FIG. 8 is a bar graph which shows the chemical transformation of aphotolabile molecule (acetylated o-NB) in solution after short exposureto UV-A light using a fiber-optic. The extent of chemical transformationwas 41% after the dose applied. FIG. 8 demonstrates that the extent ofphotoinduced chemical transformation of the photolabile molecule can betuned based upon dose applied to the system and that this chemicaltransformation can be monitored by NMR and UV-Vis. The degree ofchemical transformation can be varied based on factors including thedose intensity, dose time, as well as wavelength of the light applied.This photolabile molecule or others, as described in this disclosure,may be included in the polymer mass to yield photoreversible properties.

Example 9 Reduction in Mechanical Properties of the Device afterExposure to UV Light

The graphs in FIGS. 9A-9C demonstrate: G′ (storage modulus) (FIG. 9A),G′' (loss modulus) (FIG. 9B), C) N (normal force) (FIG. 9C) for ahydrogel that contains the photolabi molecule described in Example 8 andthis disclosure, upon exposure to ultraviolet light over time (50minutes). As a result of the UV-exposure, the G′, G″, and N decreasedsubstantially. For example, in the first 10 minutes, the G′ decreased by75.4% and in the first 2.0 minutes, the G′ decreased by 96,2%. After 10minutes, the gels were dissolved into a liquid state and thus, werereversed.

Example 10 Cytocompatibility of IJV Light

FIG. 10 shows the cytocompatibility of a stimulus (in this example,UV-light) as a reversal method. In this experiment, UV-light was exposeddirectly to Leydig cells, which are found in the testes, and then themetabolic activity of those cells was measured using an Alamar blueassay. There was no statistical difference between the cells not exposedto the stimulus and the cells exposed to 3.75 J, 7.5 J, and 15 J oflight.

The present invention has been described with reference to particularembodiments having various features. light of the disclosure providedabove, it will be apparent to those skilled in the art that variousmodifications and variations can be made in the practice of the presentinvention without departing from the scope or spirit of the invention.Any apparatus, system or device described herein may be used in anymethod described herein or any method otherwise available at any time.Likewise, any method described herein can be performed by any apparatus,device, or system described herein or otherwise available at any time.One skilled in the art will recognize that the disclosed features may beused singularly, in any combination, or omitted based on therequirements and specifications of a given application or design. Whenan embodiment refers to “comprising” certain features, it is to beunderstood that the embodiments can alternatively “consist of” or“consist essentially of” any one or more of the features. Otherembodiments of the invention will be apparent to those skilled in theart from consideration of the specification and practice of theinvention.

It is noted in particular that where a range of values is provided inthis specification, each value between the upper and lower limits ofthat range is also specifically disclosed. The upper and lower limits ofthese smaller ranges may independently be included or excluded in therange as well. The singular forms “a,” “an,” and “the” include pluralreferents unless the context clearly dictates otherwise. It is intendedthat the specification and examples be considered as exemplary in natureand that variations that do not depart from the essence of the inventionfall within the scope of the invention. Further, all of the referencescited in this disclosure are each individually incorporated by referenceherein in their entireties and as such are intended to provide anefficient way of supplementing the enabling disclosure of this inventionas well as provide background detailing the level of ordinary skill inthe art.

1. A composition comprising: one or more species with a diameter of lessthan 1 μm in solvent; wherein the one or more species are capable offorming an implantable network with pores of less than or equal to 3 μm;wherein the one or more species and/or the implantable network arecapable of being injected into a bodily lumen; and wherein theimpla.ntable network has a life-span of 6 months or greater in vivo. 2.A composition for an occlusive implant comprising: a multi-armpolyethylene glycol terminated with thiol crosslinked with a multi-armpolyethylene glycol terminated with a maleimide; and wherein thecomposition is in a form capable of being extruded from a needle.
 3. Acomposition for an occlusive implant comprising: a multi-armpolyethylene glycol terminated with a thiol crosslinked in situ with amulti-arm polyethylene glycol terminated with a tnaleimide,
 4. Thecomposition of claim 1, wherein one or more of the species comprises oneor more of natural or synthetic monomers, polymers, copolymers or blockcopolymers, biocompatible monomers, polymers, copolymers or blockcopolymers, polystyrene, neoprene, polyetherether 10 ketone (PEEK),carbon reinforced PEEK, polyphenylene, polyetherketoneketone (PEKK),polyaryletherketone (PAEK), polyphenylsulphone, polysulphone,polyurethane, polyethylene, low-density polyethylene (L,DPE), linearlow-density polyethylene (LLDPE), high-density polyethylene (HDPE),polypropylene, polyetherketoneetherketoneketone (PEKEKK), nylon,fluoropolymers, polytetrafluoroethylene (PTFE or TEFLON®), TEFLON® TFE(tetrafluoroethylene), polyethylene terephthalate (PET or PETE), TEFLON®FEP (fluorinated ethylene propylene), TEFLON® PFA (perfluoroalkoxyalkane), and/or polymethylpentene (PMP) styrene maleic anhydride,styrene maleic acid (SMA), polyurethane, silicone, polymethylmethacrylate, polyacrylonitrile, poly (carbonate-urethane), poly(vinylacetate), nitrocellulose, cellulose acetate, urethane,urethane/carbonate, polylactic acid, polyacrylamide (PAAM), poly(N-isopropylacrylamine) (PNIPAM), poly (vinylmethylether), poly(ethylene oxide), poly (ethyl (hydroxyethyl) cellulose), polyoxazoline(POx), polylactide (PLA), polyglycolide (PGA),poly(lactide-co-glycolide) PLGA, poly(e-caprolactone), polydiaoxanone,polyanhydride, trimethylene carbonate, poly(β-hydroxybutyra.te),poly(g-ethyl glutamate), poly(DTH-iminocarbonate), poly(bisphenol Aiminocarbonate), poly(orthoester) (POE), polycyanoacrylate (PCA),polyphosphazene, polyethyleneoxide (PEO), polyethyleneglycol (PEG) orany of its derivatives, polyacrylacid (PAA), polyacrylonitrile (PAN),polyvinylacrylate (PVA), polyvinylpyrrolidone (PVP), polyglycolic lacticacid (PGLA), poly(2-hydroxypropyl methacrylamide) (pHPMAm), poly(vinylalcohol) (PVOH), PEG diacrylate (PEGDA), poly(hydroxyethyl methacrylate)(pHEMA), N-isopropylacrylamide (NIPA), poly(vinyl alcohol) poly(acrylicacid) (PVOH-PAA), collagen, silk, fibrin, gelatin, hyaluron, cellulose,chitin, dextran, casein, albumin, ovalbumin, heparin sulfate, starch,agar, heparin, alginate, fibronectin, keratin, pectin, elastin, ethylenevinyl acetate, ethylene vinyl alcohol (EVOH), polyethylene oxide, PLA orPLLA (poly(L-lactide) or pol(L-lactic acid)), poly(D.L-lactic acid),poly(D,L-lactide), polydimethylsiloxane or dimethicone (PDMS),poly(isopropyl acrylate) (PIPA), polyethylene vinyl acetate (PEVA), PEGstyrene, polytetraflurorethylene RFE, TEFLON® RFE, KRYTOX® RFE,fluorinated polyethylene (FLPE or NALGENE®, methyl palmitate,temperature responsive polymers, poly(N-isopropylacry I amide) (NIPA),polycarbonate, polyethersul fone, polycaprolactone, polymethylmethacrylate, polyisobutylene, nitrocellulose, medical grade silicone,cellulose acetate, cellulose acetate butyrate, polyacrylonitrile,poly(la.cti de-co-caprolactone (PLCL), and/or chitosan.
 5. Thecomposition of claim 1, wherein one or more of the species isfunctionalized with a group, including but not limited to, acetic acid,acetylene, acrylate, alkyl, free amine, amine (HCl salt), ATRPinitiator, azide, biotin, butyrate, carboxylic acid, chloroformate,epoxide, hydroxyl, isocyanate, methacrylate, nitrophenyl carbonate, NHSester, aminooxy, polycaprolactone, polylactide, propionic acid, RAFTCTA, succinimidyl, succinimidyl carboxymethyl, succinimidyl glutaramide,succinimidyl glutarate, thiol, tosylate, vinyl ether, vinylsulfone,and/or bis-MPA Dendron.
 6. The composition of claim 1, wherein one ormore of the species is heterobifunctional, homobifunctional,monofunctional, dendrimer, multi-arm, block co-polymer, or randomco-polymer.
 7. The composition of claim 1, wherein one or more of thespecies are capable of crosslinking.
 8. The composition of claim 1,wherein one or more of the species are capable of crosslinking andforming an implantable network by way of a bio-orthogonal reaction. 9.The composition of claim 1, wherein the solvent comprises an aqueoussolvent, organic solvent, or combination of organic and aqueous solvent.10. The composition of claim 2, wherein the multi-arm polyethyleneglycol terminated with thiol and/or the multi-arm polyethylene glycolterminated with a maleimide are dissolved in an aqueous solvent orcombination of aqueous and organic solvent prior to forming thecomposition.
 11. The composition of claim 3, wherein the multi-armpolyethylene glycol terminated with thiol and/or the multi-armpolyethylene glycol terminated with a maleimide are dissolved in anaqueous solvent or combination of aqueous and organic solvent prior toforming the composition.
 12. The composition of claim 1, wherein one ormore of the species is a polymer with a weight percent ranging fromabout 1 to 30% in solvent.
 13. The composition of claim 2, wherein themulti-arm polyethylene glycol terminated with thiol and/or the multi-armpolyethylene glycol terminated with a maleimide have a weight percentranging from about 1 to 30% in solvent.
 14. The composition of claim 3,wherein the multi-arm polyethylene glycol terminated with thiol and/orthe multi-arm polyethylene glycol terminated with a maleimide have aweight percent ranging from about 1 to 30% in solvent.
 15. Thecomposition of claim 1, wherein the species may be linear, Y-shaped,3-arm, 4-arm, 6-arm, 8-arm, branched, block-co-polymer,random-co-polymer, or gradient-co-polymer,
 16. The composition of claim2, wherein the polyethylene glycol may he linear, Y-shaped, 3-arm,4-arm, 6-arm, or 8-arm.
 17. The composition of claim 3, wherein thepolyethylene glycol may be linear, Y-shaped, 3-arm, 4-arm, 6-arm, or8-arm.
 18. The composition of claim 1, wherein the composition has agelation rate ranging from 0.1 seconds to 30 minutes at bodytemperature.
 19. The composition of claim 2, wherein the composition hasa gelation rate ranging from 0.1 seconds to 30 minutes at bodytemperature.
 20. The composition of claim 3, wherein the composition hasa gelation rate ranging from 0.1 seconds to 30 minutes at bodytemperature.